Inhibitors of beta-secretase

ABSTRACT

The present invention relates to compounds represented by Structural Formula (I): 
                         
or a pharmaceutically acceptable salt thereof. Definitions for the variables are provided herein.

CROSS-REFERENCED TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.13/575,679, filed Nov. 14, 2012, which is a 35 U.S.C. §371 nationalstage filing of International Application No. PCT/US2011/025912, filedFeb. 23, 2011, which claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/307,625, filed on Feb. 24, 2010, entitled“Inhibitors of Beta-Secretase”. The entire teachings of all of the aboveapplications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

β-Amyloid deposits and neurofibrillary tangles are two major pathologiccharacterizations associated with Alzheimer's disease (AD). Clinically,AD is characterized by the loss of memory, cognition, reasoning,judgment, and orientation. Also affected, as the disease progresses, aremotor, sensory and linguistic abilities until global impairment ofmultiple cognitive functions occurs. These cognitive losses take placegradually, but typically lead to severe impairment and eventual death in4-12 years.

β-Amyloid deposits are predominantly an aggregate of Aβ peptide, whichin turn is a product of the proteolysis of amyloid precursor protein(APP). More specifically, Aβ peptide results from the cleavage of APP atthe C-terminals by one or more γ-secretases, and at the N-terminus byβ-secretase enzyme (BACE), also known as aspartyl protease, as part ofthe β-amyloidogenic pathway.

BACE activity is correlated directly to the generation of Aβ peptidefrom APP, and studies increasingly indicate that the inhibition of BACEinhibits the production of Aβ peptide.

Amyloidogenic plaques and vascular amyloid angiopathy also characterizethe brains of patients with Trisomy 21 (Down's Syndrome), HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), andother neurodegenerative disorders. Neurofibrillary tangles also occur inother neurodegenerative disorders including dementia-inducing disorders.

Recently, Amyloid-β (Aβ) has been reported to be implicated in thedevelopment of RGC apotosis in glaucoma, with evidence ofcaspase-3-mediated abnormal amyloid precursor protein processing,increased expression of Aβ in RGCs in experimental glaucoma anddecreased vitreous Aβ levels (consistent with retinal Aβ deposition) inpatients with glaucoma.

The present invention provides compounds that are BACE inhibitors andare useful as therapeutic agents in the treatment, prevention andamelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient.

SUMMARY OF THE INVENTION

One embodiment of the invention is a compound represented by StructuralFormula (I):

or a pharmaceutically acceptable salt thereof.

is a double bond or a single bond.

W is C when

is a double bond, or W is N or CR⁰ when

is a single bond.

Ring B is a 5 or 6 membered carbocycle or a 5 or 6-membered heterocyclecontaining 1 to 3 heteroatoms independently selected from O, N or S,wherein the heterocycle represented by Ring B is optionally substitutedwith one or more groups represented by R⁰, and provided that Ring Bcontains no adjacent ring oxygen atoms, no adjacent ring sulfur atomsand no ring oxygen atom adjacent to a ring sulfur atom.

X is —O— or —C(R³R⁴)—.

Each R⁰ is independently selected from —H, —CN, —NO₂, halogen, —OR⁵,—NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(O)₂R⁵, —S(O)₂NR¹²R¹³, —C(═O)OR⁵, —OC(═O)R⁵,—C(═S)OR⁵, —OC(═S)R⁵, —C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³,—NR¹¹C(═S)R⁵, —NR¹¹(C═O)OR⁵, —O(C═O)NR¹²R¹³, —NR¹¹(C═S)OR⁵,—O(C═S)NR¹²R¹³, —NR¹¹(C═O)NR¹²R¹³, —NR¹¹(C═S)NR¹²R¹³, —C(═O)R⁵,—C(═S)R⁵, (C₁-C₆)alkyl, (C₃-C₄)cycloalkyl and(C₃-C₄)cycloalkyl(C₁-C₃)alkyl and wherein each (C₁-C₆)alkyl and(C₁-C₃)alkoxy represented by R⁰ are optionally substituted with 1 to 5substituents independently selected from the group consisting ofhalogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy, and —NR⁶R⁷, or two R⁰ together with the ring carbon atomto which they are attached form a (C₃-C₆)cycloalkyl, optionallysubstituted with halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy, and —NR⁶R⁷.

R¹ is —H, —OH, —(C₁-C₄)alkoxy, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, wherein each alkyl, aryl and heteroaryl isoptionally substituted with 1 to 5 substituents independently selectedfrom halogen, —CN, —OH, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₃)alkoxyand halo(C₁-C₃)alkoxy.

Each R² is independently selected from a) —H, halogen, —CN, —NO₂, —OR⁵,—NR⁶R⁷, —NR¹¹S(O)₂R⁵, —S(O)₂NR¹²R¹³, —C(═O)OR⁵, —OC(═O)R⁵, —C(═S)OR⁵,—OC(═S)R⁵, —C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —NR¹¹C(═S)R⁵,—NR¹¹(C═O)OR⁵, —O(C═O)NR¹²R¹³, —NR¹¹(C═S)OR⁵, —O(C═S)NR¹²R¹³,—NR¹¹(C═O)NR¹²R¹³, —NR¹¹(C═S)NR¹²R¹³, —C(═O)R⁵, —C(═S)R⁵; and b)(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₂-C₆)alkynyl,(C₄-C₈)cycloalkenyl, (C₃-C₉)heterocycloalkyl,(C₃-C₉)heterocycloalkyl(C₁-C₆)alkyl,(C₃-C₉)heterocycloalkyl(C₂-C₆)alkynyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₂-C₆)alkynyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, andheteroaryl(C₂-C₆)alkynyl, wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(C₂-C₆)alkynyl, (C₄-C₈)cycloalkenyl,(C₃-C₉)heterocycloalkyl, (C₃-C₉)heterocycloalkyl(C₁-C₆)alkyl,(C₃-C₉)heterocycloalkyl(C₂-C₆)alkynyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₂-C₆)alkynyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, andheteroaryl(C₂-C₆)alkynyl is optionally substituted with 1 to 5substituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(O)₂R⁵,—S(O)₂NR¹²R¹³, —C(═O)OR⁵, —OC(═O)R⁵, —C(═S)OR⁵, —OC(═S)R⁵,—C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —NR¹¹C(═S)R⁵, —NR¹¹(C═O)OR⁵,—O(C═O)NR¹²R¹³, —NR¹¹(C═S)OR⁵, —O(C═S)NR¹²R¹³, —NR¹¹(C═O)NR¹²R¹³,—NR¹¹(C═S)NR¹²R¹³, —C(═O)R⁵, —C(═S)R⁵, (C₁-C₆)alkyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₈)cycloalkenyl, (C₃-C₉)heterocycloalkyl,(C₂-C₆)alkenyl, halo(C₁-C₆)alkyl,—(C₁-C₆)alkylene-NR¹¹—SO₂—(C₁-C₃)alkyl, hydroxy(C₁-C₆)alkyl,cyano(C₁-C₆)alkyl, —(C₁-C₆)alkylene-NR¹¹—C(═O)—(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₆)alkoxy(C₁-C₃)alkyl, aryl, andheteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl andheteroaryl groups in the substituents on the groups represented by R₂are each optionally substituted with 1 to 3 substituents independentlyselected from halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy and (C₁-C₃)alkoxy(C₁-C₆)alkyl.

R³ and R⁴ are each independently —H, halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy or(C₁-C₃)alkoxy(C₁-C₄)alkyl.

R⁵ is selected from the group consisting of —H, (C₁-C₃)alkyl,halo(C₁-C₄)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkyl and phenyl optionally substituted withhalogen, —CN, —NO₂, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl or(C₁-C₃)alkoxy(C₁-C₃)alkyl.

R⁶ is —H or (C₁-C₃)alkyl.

R⁷ is —H, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl.

R⁸ and R⁹, together with the carbon to which they are attached, formring A, which is a 3-9 membered cycloalkyl optionally substituted with 1to 4 substituents independently selected from the group consisting ofhalogen, —CN, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(═O)₂R⁵, —C(═O)OR⁵,—C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —C(═O)R⁵, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl andheteroaryl(C₁-C₆)alkyl, wherein each of the (C₁-C₆)alkyl,(C₂-C₆)alkenyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl andheteroaryl(C₁-C₆)alkyl substituents on Ring A is optionally substitutedwith 1 to 5 substituents independently selected from the groupconsisting of (C₁-C₆)alkyl, halogen, —CN, —OH, —NR¹¹SO₂(C₁-C₃)alkyl,—NR¹¹C(═O)—(C₁-C₃)alkyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxyand (C₁-C₃)alkoxy(C₁-C₆)alkyl, and wherein Ring A is optionally fused tophenyl group optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, —CN, —OH, —NR¹¹SO₂(C₁-C₃)alkyl, —NR¹¹C(═O)—(C₁-C₃)alkyl,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy and(C₁-C₃)alkoxy(C₁-C₆)alkyl.

R¹¹ is —H or (C₁-C₃)alkyl.

R¹² is —H or (C₁-C₃)alkyl.

R¹³ is —H, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl(C₁-C₃)alkylor (C₁-C₃)alkoxy(C₁-C₃)alkyl.

i is 0, 1 or 2.

p is 1, 2, 3 or 4.

Another embodiment of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier or diluent and acompound represented by Structural Formula (I) or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is a method of inhibiting BACEactivity in a subject in need of such treatment. The method comprisesadministering to the subject an effective amount of a compoundrepresented by Structural Formula (I) or a pharmaceutically acceptablesalt thereof.

Another embodiment of the invention is a method of treating a BACEmediated disorder in a subject. The method comprises administering tothe subject an effective amount of a compound represented by StructuralFormula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for inhibiting BACE activity in asubject.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating a BACE mediateddisorder in a subject.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor inhibiting BACE activity in a subject.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor treating a BACE mediated disorder in a subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds represented by theStructural Formula (I), or a pharmaceutically acceptable salt thereof.Values and alternative values for the variables in Structural Formula(I) and the other structural formulas described herein are provided inthe following paragraphs.

R⁰ is as described above for Structural Formula (I). Alternatively, R⁰is —H, (C₁-C₆)alkyl, (C₁-C₃)alkoxy, —CN, —NR⁶R⁷, wherein each(C₁-C₆)alkyl and (C₁-C₃)alkoxy are optionally substituted with 1 to 5substituents independently selected from the group consisting ofhalogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy, and —NR⁶R⁷, or two R⁰ together with the ring carbon atomto which they are attached form a (C₃-C₆)cycloalkyl, optionallysubstituted with halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy, and —NR⁶R⁷. In anotheralternative, each R⁰, when present, is independently selected from thegroup consisting of —H, —F, —CN, -Me, -Et, —OMe, —CF₃ and —NH₂, or twoR⁰ together with the carbon atom to which they are attached form acyclopropyl ring.

R¹ is as described above for Structural Formula (I). Alternatively, R¹is a —H or a (C₁-C₃)alkyl. In another alternative, R¹ is —H.

R² is as described above for Structural Formula (I). In one alternative,each R² is independently selected from the group consisting of —H,halogen, —CN, —NO₂, —OR⁵, —C(═O)NR¹²R¹³, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, phenyl(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₄-C₈)cyclohexenyl, phenyl, pyridyl, thiazolyl, pyridazinyl,pyridazinone, pyridinone, thiophenyl, pyrrolyl, pyrimidinyl, pyrazinyl,indolyl, pyrrolidinyl, piperazinyl and morpholinyl, each of the(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl(C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₈)cyclohexenyl, phenyl, pyridinyl, thiazolyl,pyridazinyl, pyridazinone, pyridinone, thiophenyl, pyrrolyl,pyrimidinyl, pyrazinyl, indolyl, pyrrolidinyl, piperazinyl andmorpholinyl is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halogen, —OH, —CN,—NO₂, (C₁-C₆)alkyl, (C₂-C₆)alkynyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkoxy(C₁-C₆)alkyl, —NR⁶R⁷ and—SO₂R^(c).

Alternatively, R² is —Br, —Cl, —CN, —OR⁵, (C₁-C₆)alkyl, (C₂-C₆)alkynyl,phenyl or pyridinyl, wherein each of the (C₁-C₆)alkyl, (C₂-C₆)alkynyl,phenyl and pyridinyl is optionally substituted with 1 to 3 substituentsindependently selected from —F, —Cl, —Br, —CN, (C₃-C₆)cycloalkyl,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy and halo(C₁-C₃)alkoxy.

In another alternative embodiment, each R² is independently selectedfrom the group consisting of —Br, —Cl, —CN, cyclopropylethyl,cyclopropylethynyl, cyclopropylmethoxy, 5-trifluoromethyl-2-pyridyl,2-pyridyl, 3-chloro-5-fluorophenyl, 3-cyanophenyl,3-trifluoromethoxyphenyl and methoxy.

R³ and R⁴ are as described above for Structural Formula (I).Alternatively, R³ and R⁴ are —H.

R⁵ is as described above for Structural Formula (I). In anotherembodiment, R⁵ is selected from the group consisting of —H,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₃)alkyl and phenyl optionallysubstituted with halogen, —CN, —NO₂, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl or(C₁-C₃)alkoxy(C₁-C₃)alkyl. Alternatively, R⁵ is selected from the groupconsisting of —H, -Me, —CF₃ and cyclopropylmethyl.

R⁶ and R⁷ are as described above for Structural Formula (I).Alternatively, R⁶ and R⁷ are both —H.

R⁸ and R⁹ and Ring A are as described above for Structural Formula (I).

Alternatively, ring A is represented by the following structuralformula:

wherein R¹⁹ and R²⁰ are each independently selected from —H, halogen,—CN, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(═O)₂R⁵, —C(═O)OR⁵, —C(═O)NR¹²R¹³,—NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —C(═O)R⁵, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,aryl, aryl(C₁-C₆)alkyl, heteroaryl and heteroaryl(C₁-C₆)alkyl, whereineach of the (C₁-C₆)alkyl, (C₂-C₆)alkenyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl groups represented by R₁₉ and R₂₀is optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of halogen, —CN, —OH,—NR¹¹SO₂(C₁-C₃)alkyl, —NR¹¹C(═O)—(C₁-C₃)alkyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy and (C₁-C₃)alkoxy(C₁-C₆)alkyl. Inanother alternative, R¹⁹ and R²⁰ are each independently selected from—H, halogen, —CN, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(═O)₂R⁵, —C(═O)OR⁵,—C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —C(═O)R⁵ and (C₁-C₆)alkyl,wherein the (C₁-C₆)alkyl group represented by R₁₉ and R₂₀ is optionallysubstituted with 1 to 5 substituents independently selected from thegroup consisting of halogen, —CN, —OH, —NR¹¹SO₂(C₁-C₃)alkyl,—NR¹¹C(═O)—(C₁-C₃)alkyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxyand (C₁-C₃)alkoxy(C₁-C₆)alkyl. Alternatively, R²⁰ is —H and R¹⁹ is —OH,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy or (C₁-C₃)alkoxy(C₁-C₃)alkoxy.

In another alternative, Ring A is represented by:

and R¹⁹ is —H, —OH, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy or(C₁-C₃)alkoxy(C₁-C₃)alkoxy.

R¹¹ is as described above for Structural Formula (I). Alternatively, R¹¹is —H or (C₁-C₃)alkyl. In another alternative, R¹¹ is —H.

R¹² and R¹³ are as described above for Structural Formula (I).Alternatively, R¹² and R¹³ are both —H.

R¹⁵ is as described above for Structural Formula (I). Alternatively, R¹⁵is —H or (C₁-C₆)alkyl. In another alternative, R₁₅ is —H.

In one embodiment, X is as described above for Structural Formula (I).Alternatively, X is —O— or —CH₂—. In another alternative, X is —O—. Inyet another alternative embodiment, X is —CH₂—.

In one embodiment, i is as described above for Structural Formula (I).Alternatively, i is 0. In another alternative embodiment, i is 2.

In one embodiment, p is as described above for Structural Formula (I).In another embodiment, p is 2. Alternatively, p is 1.

Ring B is a monocyclic carbocycle or a monocyclic heterocycle, whereinthe carbocycle or the heterocycle is optionally substituted with one ormore R⁰ provided that Ring B contains no adjacent ring oxygen atoms, noadjacent ring sulfur atoms and no ring oxygen atom adjacent to a ringsulfur atom. In another embodiment, ring B is a 5 or 6-memberedheterocycle containing 1 to 3 heteroatoms independently selected fromthe group consisting of N, O and S, wherein the heterocycle isoptionally substituted with one or more R⁰, provided that Ring Bcontains no adjacent ring oxygen atoms, no adjacent ring sulfur atomsand no ring oxygen atom adjacent to a ring sulfur atom. Alternatively,ring B is a phenyl ring optionally substituted with one or more R⁰.

W is C when

is a double bond, or W is N or CR⁰ when

is a single bond.

In a 1^(st) embodiment, the compound of the present invention isrepresented by s structural formula selected from:

or a pharmaceutically acceptable salt thereof, wherein:

a is 1, 2, 3 or 4;

b is 1, 2 or 3;

c is an integer from 1 to 8;

d is an integer from 1 to 6;

e is 1, 2, 3 or 4; and

f is 1 or 2.

The remainder of the variables are as described above for StructuralFormula (I). Alternatively for Structural Formulas (II)-(VIII), X is—CH₂—. In another alternative for Structural Formulas (II)-(VIII), X is—O—.

In a 2^(nd) embodiment, the compound of the present invention isrepresented by a structural formula selected from:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described above for Structural Formulas (II)-(VIII) in the 1stembodiment.

In a 3^(rd) embodiment, the compound of the invention is represented bya structural formula selected from Structural Formulas (I), (II)-(VIII),(IIa)-(VIIIa) and (IIb)-(VIIIb), wherein: ring A (or R⁸ and R⁹ takentogether with the carbon atom to which they are bonded) is representedby Structural Formula (B):

wherein R¹⁹ and R²⁰ are each independently selected from —H, halogen,—CN, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(═O)₂R⁵, —C(═O)OR⁵, —C(═O)NR¹²R¹³,—NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —C(═O)R⁵, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,aryl, aryl(C₁-C₆)alkyl, heteroaryl and heteroaryl(C₁-C₆)alkyl, whereineach of the (C₁-C₆)alkyl, (C₂-C₆)alkenyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl groups represented by R₁₉ and R₂₀is optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of halogen, —CN, —OH,—NR¹¹SO₂(C₁-C₃)alkyl, —NR¹¹C(═O)—(C₁-C₃)alkyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy and (C₁-C₃)alkoxy(C₁-C₆)alkyl. Theremainder of the variables are as described above in the 1^(st) or2^(nd) embodiment. Alternatively, R²⁰ is —H and R¹⁹ is —OH,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy or (C₁-C₃)alkoxy(C₁-C₃)alkoxy; and theremainder of the variables are as described above in the 1^(st) or2^(nd) embodiment.

In a 4th embodiment, the compound of the present invention isrepresented by a structural formula selected from:

or a pharmaceutically acceptable salt thereof, wherein:

R⁰ is —H, (C₁-C₆)alkyl, (C₁-C₃)alkoxy, —CN, —NR⁶R⁷, wherein each(C₁-C₆)alkyl and (C₁-C₃)alkoxy are optionally substituted with 1 to 5substituents independently selected from the group consisting ofhalogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy, and —NR⁶R⁷, or two R⁰ together with the ring carbon atomto which they are attached form a (C₃-C₆)cycloalkyl, optionallysubstituted with halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy, and —NR⁶R⁷;

R¹⁹ is —OH, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy or(C₁-C₃)alkoxy(C₁-C₃)alkoxy;

a is 1;

b is 1;

c is 1;

d is 1 or 2;

e is 1; and

f is 1; and

the remainder of the variables are as described above for StructuralFormulas (II)-(VIII) in the 1^(st) embodiment.

In a 5^(th) embodiment, the compound of the invention is represented bya structural formula selected from Structural Formulas (I), (II)-(VIII),(IIa)-(VIIIa), (IIb)-(VIIIb), (IIc)-(VIIIc) and (IId)-(VIIId):

R¹ is a —H or a (C₁-C₃)alkyl;

each R² is independently selected from the group consisting of —H,halogen, —CN, —NO₂, —OR⁵, —C(═O)NR¹²R¹³, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, phenyl(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₄-C₈)cycloalkenyl, phenyl, pyridyl, thiazolyl, pyridazinyl,pyridazinone, pyridinone, thiophenyl, pyrrolyl, pyrimidinyl, pyrazinyl,indolyl, pyrrolidinyl, piperazinyl and morpholinyl, each of the(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl(C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₈)cyclohexenyl, phenyl, pyridinyl, thiazolyl,pyridazinyl, pyridazinone, pyridinone, thiophenyl, pyrrolyl,pyrimidinyl, pyrazinyl, indolyl, pyrrolidinyl, piperazinyl andmorpholinyl is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halogen, —OH, —CN,—NO₂, (C₁-C₆)alkyl, (C₂-C₆)alkynyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkoxy(C₁-C₆)alkyl, —NR⁶R⁷ and—SO₂R^(c). Each R² is independently selected from —Br, —Cl, —CN, —OR⁵,(C₁-C₆)alkyl, (C₂-C₆)alkynyl, phenyl and pyridinyl, wherein each of the(C₁-C₆)alkyl, (C₂-C₆)alkynyl, phenyl and pyridinyl is optionallysubstituted with 1 to 3 substituents independently selected from —F,—Cl, —Br, —CN, (C₃-C₆)cycloalkyl, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy and halo(C₁-C₃)alkoxy;

each R⁰, when present, is independently selected from the groupconsisting of —H, halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy and —NR⁶R⁷, or two R⁰ together with the carbon atom towhich they are attached form a (C₃-C₆)cycloalkyl optionally substitutedwith 1 to 3 substituents independently selected from halogen, —CN,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy and(C₁-C₃)alkoxy(C₁-C₆)alkyl; and

the remainder of the variables are as described above in the 1^(st),2^(nd), 3^(rd) or 4^(th) embodiment.

In a 6^(th) embodiment, the compound of the invention is represented bya structural formula selected from Structural Formulas (I), (II)-(VIII),(IIa)-(VIIIa), (IIb)-(VIIIb), (IIc)-(VIIIc) and (IId)-(VIIId):

R⁵ is selected from the group consisting of —H, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkyl and phenyl optionally substituted withhalogen, —CN, —NO₂, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl or(C₁-C₃)alkoxy(C₁-C₃)alkyl;

R⁶ is —H or (C₁-C₃)alkyl;

R⁷ is —H, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl;

R¹¹ is —H or (C₁-C₃)alkyl;

R¹² is —H or (C₁-C₃)alkyl; and

R¹³ is (C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl(C₁-C₃)alkyl or(C₁-C₃)alkoxy(C₁-C₃)alkyl; and

the remainder of the variables are as described above in the 1^(st),2^(nd), 3^(rd), 4^(th) or 5^(th) embodiment.

In a 7^(th) embodiment, the compound of the invention is represented bya structural formula selected from Structural Formulas (I), (II)-(VIII),(IIa)-(VIIIa), (IIb)-(VIIIb), (IIc)-(VIIIc) and (IId)-(VIIId):

R¹ is —H;

each R² is independently selected from the group consisting of —Br, —Cl,—CN, cyclopropylethyl, cyclopropylethynyl, cyclopropylmethoxy,5-trifluoromethyl-2-pyridyl, 2-pyridyl, 3-chloro-5-fluorophenyl,3-cyanophenyl, 3-trifluoromethoxyphenyl and methoxy; and

each R⁰, when present, is independently selected from the groupconsisting of —F, —CN, -Me, -Et, —OMe, —CF₃ and —NH₂, or two R⁰ togetherwith the carbon atom to which they are attached form a cyclopropyl ring;and

the remainder of the variables are as described above in the in the1^(st), 2^(nd), 3^(th), 4^(th), 5^(th) or 6^(th) embodiment.

In an 8^(th) embodiment, the compound of the invention is represented bya structural formulas selected from Structural Formulas (I),(II)-(VIII), (IIa)-(VIIIa), (IIb)-(VIIIb), (IIc)-(VIIIc) and(IId)-(VIIId):

R⁵ is selected from the group consisting of -Me, —CF₃ andcyclopropylmethyl; and

R⁶, R⁷, R¹¹, R¹² and R¹³ are all —H; and

the remainder of the variables are as described above in the 1^(st),2^(nd), 3^(th), 4^(th), 5^(th) 6^(th) or 7^(th) embodiment.

Another embodiment of the present invention is directed to the compoundsdescribed in Examples 1-37, an enatiomer, a diastereomer, a tautomer ora pharmaceutically acceptable salt thereof.

GENERAL DEFINITIONS

Terms not specifically defined herein should be understood to have themeanings that would be given to them by one of skill in the art in lightof the disclosure and the context. As used in the specification,however, unless specified to the contrary, the following terms have themeaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, (C₁-C₆)alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl(C₁-C₃)alkyl” means an aryl group which is bound to a (C₁-C₃)alkylgroup, the latter of which is bound to the core or to the group to whichthe substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula, the formula shall prevail in case of anydiscrepancy.

When any variable (e.g. aryl, heterocyclyl, R¹, R² etc.) occurs morethan once in a compound, its definition on each occurrence isindependent of any other occurrence.

“Alkyl” means a saturated aliphatic branched or straight-chainmonovalent hydrocarbon radical having the specified number of carbonatoms. For example, “(C₁-C₆)alkyl” means a radical having from 1-6carbon atoms in a linear or branched arrangement. “(C₁-C₆)alkyl”includes methyl (—CH₃), ethyl (—CH₂CH₃), propyl (—CH₂CH₂CH₃ and—CH(CH₃)CH₃), butyl (—CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, CH₂CH(CH₃)CH₃ and—C(CH₃)₂CH₃,), pentyl (—CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃,—CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)CH₃, —C(CH₃)₂CH₂CH₃, —CH₂C(CH₃)₂CH₃,—CH(CH₃)CH(CH₃)CH₃ and —CH(CH₂CH₃)CH₂CH₃), and hexyl (—CH₂(CH₂)₄CH₃,—CH(CH₃)CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)CH₂CH₃,—CH₂CH₂CH₂CH(CH₃)CH₃, —C(CH₃)₂CH₂CH₂CH₃, —CH₂C(CH₃)₂CH₂CH₃,—CH₂CH₂C(CH₃)₂CH₃, —CH(CH₃)CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)CH(CH₃)CH₃,—CH(CH₃)CH₂CH(CH₃)CH₃, —CH₂CH(CH₂CH₃)CH₂CH₃, and —CH₂CH(CH(CH₃)₂)CH₃).

“Alkenyl” means branched or straight-chain monovalent hydrocarbonradical containing at least one double bond and having specified numberof carbon atoms. Alkenyl may be mono or polyunsaturated, and may existin the E or Z configuration. For example, “(C₂-C₆)alkenyl” means aradical having from 2-6 carbon atoms in a linear or branchedarrangement.

“Alkynyl” means branched or straight-chain monovalent hydrocarbonradical containing at least one triple bond and having specified numberof carbon atoms. For example, “(C₂-C₆)alkynyl” means a radical havingfrom 2-6 carbon atoms in a linear or branched arrangement.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom.“(C₁-C₄)-alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.

“Aryl”, “aryl group”, “aryl ring”, “aromatic”, “aromatic group” and“aromatic ring” are used interchangeably and mean an aromaticmonocyclic, or polycyclic hydrocarbon ring system. “Aryl” includes, butis not limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl,and anthracenyl.

The term “carbocyclyl” as used either alone or in combination withanother radical, means a monocyclic or polycyclic ring structureconsisting only of carbon containing between one and four rings. Theterm “carbocycle” refers to fully saturated and aromatic ring systemsand partially saturated ring systems and encompasses fused, spirosystems, and bridged systems.

“Cycloalkene” is an unsaturated and non-aromatic aliphatic cyclichydrocarbon radical having the specified number of carbon atoms. It canbe monocyclic, bicyclic, tricyclic, fused, bridged, or spiro. Thus,monocyclic (C₃-C₈)cycloalkene means a radical having from 3-8 carbonatoms arranged in a ring. A (C₃-C₈)cycloalkene includes cyclobutene,cyclopentene, cyclohexene, cycloheptene and cyclooctene.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radicalhaving the specified number of carbon atoms. It can be monocyclic,bicyclic, polycyclic (e.g., tricyclic), fused, bridged, or spiro. Forexample, monocyclic (C₃-C₈)cycloalkyl means a radical having from 3-8carbon atoms arranged in a monocyclic ring. A (C₃-C₈)cycloalkylincludes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctane.

Monocyclic ring systems have a single ring. They include saturated,partially saturated or unsaturated carbocyclic rings or heterocycleshaving the specified number of ring atoms.

Bicyclic ring systems have two rings that have at least one ring atom incommon. Bicyclic ring systems include fused, bridged and spiro ringsystems. The two rings can both be aliphatic (e.g., cycloalkyl orcycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or acombination thereof. The bicyclic ring systems can optionally contain 1to 3 heteroatoms in the ring structure and each heteroatom isindependently selected from the group consisting O, N and S.

A fused bicyclic ring system has two rings which have two adjacent ringatoms in common. The two rings can both be aliphatic (e.g., cycloalkylor cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or acombination thereof. For example, the first ring can be monocycliccycloalkyl or monocyclic cycloheteroalkyl, and the second ring can acycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or amonocyclic cycloheteroalkyl. For example, the second ring can be a(C₃-C₆)cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. Alternatively, the second ring can be an aryl ring, e.g.,phenyl.

A spiro bicyclic ring system has two rings which have only one ring atomin common. The rings are cycloalkyl, cycloheteroalkyl or partiallysaturated counterparts thereof. Examples of spiral bicyclic ring systeminclude, but are not limited to, spiro[2.2]pentane, spiro[2.3]hexane,spiro[13.3]heptane, spiro[2.4]heptane, spiro[13.4]octane,spiro[12.5]octane, azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane,azasprio[4.5]decane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane,3-azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane.

A bridged ring system has two rings which have three or more adjacentring atoms in common. The two rings are cycloalkyl, cycloheteroalkyl orpartially saturated counterparts thereof.

Polycyclic ring systems have more than two rings (e.g., three ringsresulting in a tricyclic ring system) and adjacent rings have at leastone ring atom in common. Polycyclic ring systems include fused, bridgedand spiro ring systems. A fused polycyclic ring system has at least tworings that have two adjacent ring atoms in common. A spiro polycyclicring system has at least two rings that have only one ring atom incommon. A bridged polycyclic ring system has at least two rings thathave three or more adjacent ring atoms in common.

“Heterocycle” means a saturated, unsaturated, or aromatic mono- orpolycyclic-ring system containing one or more heteroatoms independentlyselected from N, O or S. A heterocycle can be heteroaryl ring orheterocycloalkyl.

“Heterocycloalkyl” means a saturated 4-12 membered ring radical havingspecified number of carbon atoms in the ring. The heterocycloalkylcontains 1 to 4 heteroatoms, which may be the same or different,selected from N, O or S. The heterocycloalkyl ring optionally containsone or more double bonds and is optionally fused to one or more aromaticrings or heteroaromatic rings. It can be monocyclic, bicyclic,tricyclic, fused, bridged, or spiro. For example,(C₃-C₉)heterocycloalkyl mean a saturated ring radical containing 3-9ring atoms.

Exemplary “heterocycloalkyl” includes, but is not limited to, thefollowing exemplary structures which are not depicted as radicals aseach form may be attached through a covalent bond to any atom so long asappropriate valences are maintained:

A ring nitrogen atom in a heterocycloalkyl can be substituted, providedthat it is bonded to each of its adjacent ring atoms with a single bond.Unless otherwise indicated, exemplary substituents include alkyl,cycloalkyl, aryl, arylalkyl, heteraryl, heteroarylalkyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl or (C₁-C₃)alkylcarbonyl, each of which is optionallysubstituted with halogen, hydroxy, alkoxy, haloalkyl or alkyl(preferably (C₁-C₆)alkyl, halo(C₁-C₆)alkyl or (C₁-C₃)alkylcarbonyl, eachof which is optionally substituted with halogen, hydroxy, alkoxy,haloalkyl or alkyl). Ring sulfur atoms can optionally be mono ordi-oxygenated (i.e., —S(O) or —S(O)₂).

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groupswhere the halogens are independently selected from fluorine, chlorine,and bromine. For example, a halo(C₁-C₃)alkyl includes, but is notlimited to, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃ and —CH₂CF₂CHF₂.

“Heteroaryl” is used interchangeably with “heteroaryl group”,“heteroaryl ring”, “heteroaromatic”, “heteroaromatic group” and“heteroaromatic ring”. “Heteroaryl” means a monovalent heteroaromaticmonocyclic or polycylic ring radical. Monocyclic heteroaryl rings are 5-and 6-membered aromatic heterocyclic rings containing 1 to 4 heteroatomsindependently selected from N, O, and S. Bicyclic heteroaryl ringsinclude bicyclo[4.4.0] and bicyclo[4.3.0] fused ring systems containing1 to 4 heteroatoms independently selected from N, O, and S.

For example, “heteroaryl” includes, but is not limited to, the followingexemplary structures which are not depicted as radicals as each from maybe attached through a covalent bond to any atom so long as appropriatevalences are maintained:

“Halo(C₁-C_(n))alkoxy” means a (C₁-C_(n))alkyl radical attached throughan oxygen linking atom, wherein the (C₁-C_(n))alkyl is substituted withone or more halogens independently selected from fluorine, chlorine,bromine and iodine. For example, a halo(C₁-C₃)alkoxy includes, but isnot limited to, —OCF₃, —OCH₂CF₃, —OCHFCHF₂ and —OCH₂CF₂CHF₂.

“Hetero” refers to the replacement of at least one carbon atom member ina ring system with at least one heteroatom selected from N, S, and O. Ahetero ring may have 1, 2, 3, or 4 carbon atom members replaced by aheteroatom.

“Halogen” used herein refers to fluorine, chlorine, bromine, or iodine.

When substituted, unless otherwise indicated, suitable substituents foralkyl, alkenyl, alkkynyl, cycloalkyl, cycloalkenyl, carbocycle,heterocycle, heterocycloalkyl, aryl and heteroaryl, include halogen,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy or(C₁-C₃)alkoxy(C₁-C₄)alkyl, cyano, nitro, (C₁-C₃)alkylcarbonyl,(C₁-C₃)alkoxycarbonyl, phenyl, thienyl, furanyl and pyridyl. The phenyl,thienyl, furanyl and pryidyl are optionally further substituted withhalogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₃)alkoxy,halo(C₁-C₃)alkoxy or (C₁-C₃)alkoxy(C₁-C₄)alkyl, cyano, nitro,(C₁-C₃)alkylcarbonyl and (C₁-C₃)alkoxycarbonyl.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” The phrase “pharmaceutically acceptable” is employedherein to refer to those compounds, materials, compositions, and/ordosage forms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings and animalswithout excessive toxicity, irritation, allergic response, or otherproblem or complication, and commensurate with a reasonable benefit/riskratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Pharmaceutically acceptable saltforms include pharmaceutically acceptable acidic/anionic orbasic/cationic salts. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like.

For example, such salts include, the acetate, ascorbate,benzenesulfonate, benzoate, bezylate, bicarbonate, bitartrate, bromide,calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, ethane disulfonate, estolate,esylate, fumarate, glyceptate, gluconate, glutamate, glycolate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxymaleate, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, methanesulfonate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, oxalate, pamoate, pantothenate, phenylacetate,phosphate/diphospate, polygalacturonate, propionate, salicylate,stearate, subacetate, succinate, sulfamide, sulfate, tannate, tartrate,teoclate, tosylate, triethiodide, ammonium, benzathine, chloroprocaine,colline, diethanolamine, ethylenediamine, meglumine and procaine salts.Further pharmaceutically acceptable salts can be formed with cationsfrom metals like aluminium, calcium, lithium, magnesium, potassium,sodium, zinc and the like. (also see Pharmaceutical salts, Birge, S. M.et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to the other stereoisomers.When a single enantiomer is named or depicted by structure, the depictedor named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight optically pure. Percent optical purity by weight is the ratio ofthe weight of the enantiomer over the weight of the enantiomer plus theweight of its optical isomer.

The disclosed compounds of the invention are BACE inhibitors fortreating, preventing or ameliorating disorders or diseases characterizedby elevated β-amyloid deposits or β-amyloid levels in a subject. Thepresent invention also provides a method for the treatment of a disorderrelated to or associated with excessive BACE activity in a patient inneed thereof which comprises administering to said patient an effectiveamount of a disclosed compound or a pharmaceutically acceptable saltthereof. The present invention also provides methods for inhibiting theactivity of BACE in a subject in need thereof, comprising administeringto a subject and/or contacting a receptor thereof with an effectiveamount of at least one disclosed compound or a pharmaceuticallyacceptable salt thereof. The present invention also provides methods ofameliorating β-amyloid deposits in a subject in need thereof, comprisingadministering to said subject an effective amount of at least onedisclosed compound or a pharmaceutically acceptable salt thereof.

As such, the disclosed BACE inhibitors can be used to treatneurodegenerative disorders, disorders characterized by cognitivedecline, cognitive impairment, dementia and diseases characterized byproduction of β-amyloid deposits or neurofibrillary tangles.

Exemplary diseases or disorders that can be treated by the disclosedBACE inhibitors include Alzheimer's disease, Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-typle (HCHWA-D), senile dementia, cerebral amyloid angiopathy,degenerative dementia, dementias of mixed vascular and degenerativeorigin, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy and dementia associatedwith cortical basal degeneration, diffuse Lewy body type of Alzheimer'sdisease and glaucoma.

Accordingly, the present invention relates to a disclosed compound or apharmaceutically acceptable salt thereof as a medicament.

In a further embodiment, the present invention relates to methods forthe treatment or prevention of above-mentioned diseases and conditions,which method comprises the administration of an effective amount of adisclosed compound or a pharmaceutically acceptable salt thereof.

The invention includes a therapeutic method for treating or amelioratingan BACE mediated disorder in a subject in need thereof comprisingadministering to a subject in need thereof an effective amount of adisclosed compound or a pharmaceutically acceptable salt thereof orcomposition thereof.

Administration methods include administering an effective amount (i.e.,an effective amount) of a compound or composition of the invention atdifferent times during the course of therapy or concurrently in acombination form. The methods of the invention include all knowntherapeutic treatment regimens.

As used herein, the term “subject” and “patient” may be usedinterchangeably, and means a human in need of treatment.

As used herein, the term “treating” or “treatment” refers to obtainingdesired pharmacological and/or physiological effect. The effect can beprophylactic or therapeutic, which includes achieving, partially orsubstantially, one or more of the following results: partially ortotally reducing the extent of the disease, disorder or syndrome;ameliorating or improving a clinical symptom or indicator associatedwith the disorder; delaying, inhibiting or decreasing the likelihood ofthe progression of the disease, disorder or syndrome; or partially ortotally delaying, inhibiting or reducing the likelihood of the onset ordevelopment of disease, disorder or syndrome.

“Effective amount” means that amount of active compound agent thatelicits the desired biological response in a subject. Such responseincludes alleviation of the symptoms of the disease or disorder beingtreated. The effective amount of a compound of the invention in such atherapeutic method is from about 0.01 mg/kg/day to about 1000 mg/kg/dayor from about 0.1 mg/kg/day to about 100 mg/kg/day.

“Pharmaceutically acceptable carrier” means compounds and compositionsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention and that, when appropriately administeredto an animal or human, do not produce an adverse reaction.

In one embodiment, the present invention includes combination therapyfor treating or ameliorating a disease or a disorder described herein.The combination therapy comprises administering a combination of atleast one compound represented by structural formula (A), (I) or (I′)with another compound selected from the group of, for example,gamma-secretase inhibitors; amyloid aggregation inhibitors (e.g.ELND-005); directly or indirectly acting neuroprotective and/ordisease-modifying substances; anti-oxidants (e.g. vitamin E orginkolide); anti-inflammatory substances (e.g. Cox inhibitors, NSAIDsadditionally or exclusively having Abeta lowering properties); HMG-CoAreductase inhibitors (statins); acetylcholinesterase inhibitors (e.g.,donepezil, rivastigmine, tacrine, galantamine, memantine; tacrine); NMDAreceptor antagonists (e.g. memantine); AMPA receptor agonists; AMPAreceptor positive modulators, AMPkines, monoamine receptor reuptakeinhibitors, substances modulating the concentration or release ofneurotransmitters; substances inducing the secretion of growth hormone(e.g., ibutamoren mesylate and capromorelin); CB-1 receptor antagonistsor inverse agonists; antibiotics (e.g., minocyclin or rifampicin); PDE2,PDE4, PDE5, PDE9, PDE10 inhibitors, GABAA receptor inverse agonists,GABAA receptor antagonists, nicotinic receptor agonists or partialagonists or positive modulators, alpha4beta2 nicotinic receptor agonistsor partial agonists or positive modulators, alpha7 nicotinic receptoragonists or partial agonists or positive modulators; histamine H3antagonists, 5 HT-4 agonists or partial agonists, 5HT-6 antagonists,alpha2-adrenoreceptor antagonists, calcium antagonists, muscarinicreceptor M1 agonists or partial agonists or positive modulators,muscarinic receptor M2 antagonists, muscarinic receptor M4 antagonists,metabotropic glutamate-receptor 5 positive modulators, antidepressants,such as citalopram, fluoxetine, paroxetine, sertraline and trazodone;anxiolytics, such as lorazepam and oxazepam; antiphychotics, such asaripiprazole, clozapine, haloperidol, olanzapine, quetiapine,risperidone and ziprasidone, and other substances that modulatereceptors or enzymes in a manner such that the efficacy and/or safety ofthe compounds according to the invention is increased and/or unwantedside effects are reduced. The compounds according to the invention mayalso be used in combination with immunotherapies (e.g., activeimmunisation with Abeta or parts thereof or passive immunisation withhumanised anti-Abeta antibodies or nanobodies) for the treatment of theabove-mentioned diseases and conditions.

Combination therapy includes co-administration of the compound of theinvention and said other agent, sequential administration of thecompound and the other agent, administration of a composition containingthe compound and the other agent, or simultaneous administration ofseparate compositions containing of the compound and the other agent.

Suitable preparations for administering the compounds of formula will beapparent to those with ordinary skill in the art and include for exampletablets, pills, capsules, suppositories, lozenges, troches, solutions,syrups, elixirs, sachets, injectables, inhalatives and powders etc. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.005 to 10% wt.-% of the composition as a whole.

The dosage form containing the composition of the invention contains aneffective amount of the active ingredient necessary to provide atherapeutic effect. The composition may contain from about 5,000 mg toabout 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of acompound of the invention or salt form thereof and may be constitutedinto any form suitable for the selected mode of administration.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers.

Methods of Preparation

In cases where the synthetic intermediates and final products of FormulaI described below contain potentially reactive functional groups, forexample amino, hydroxy, thiol and carboxylic acid groups, that mayinterfere with the desired reaction, it may be advantageous to employprotected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. (T. W. Greene and P. G. M. Wuts “ProtectiveGroups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999).Such protecting group manipulations are assumed in the discussion belowand not usually described explicitly. Generally, reagents in thereaction schemes are used in equimolar amounts; however, in certaincases it may be desirable to use an excess of one reagent to drive areaction to completion. This is especially the case when the excessreagent can be readily removed by evaporation or extraction. Basesemployed to neutralize HCl in reaction mixtures are generally used inslight to substantial excess (1.05-5 equivalents).

Abbreviation Meaning AcCl acetyl chloride AlCl₃ aluminum chloride Arargon B₂H₆ diborane Boc tert-butoxy carbonyl or t-butoxy carbonyl Boraxsodium borate brine saturated aqueous NaCl CH₂N₂ carbodiimide CH₃CNacetonitrile Cs₂CO₃ cesium carbonate CuBr-SMe₂ cuprous bromidemethylsulfide complex CuI cuprous iodide DCM or CH₂Cl₂ methylenechloride DEA diethylamine DIBAL-H diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine EtI ethyl iodide Et ethyl Et₂O ethyl etherEtOAc, EA ethyl acetate EtOH ethanol Et₃O⁺BF₄ ⁻ triethyloxoniumtetrafluoroborate h, hr hour HCl hydrochloric acid H₂O water H₂O₂hydrogen peroxide HCONH₂ formamide HMPA hexamethylphosphoric triamideHMPT hexamethylphosphorous triamide HOAc or AcOH acetic acid HPLC highperformance liquid chromatography K₂CO₃ potassium carbonate KCNpotassium cyanide LAH LiAlH₄ Lawesson's reagent2,4-bis(4-methoxyphenyl)-1,3,2,4- dithiadiphosphetane 2,4-disulfide LDAlithium diisopropylamide Min minute MeOH methanol MeI methyl iodide Memethyl MeNHOH methylhydroxylamine MTBA 4-(methylthio)benzoic acid Me₂Smethyl sulfide NaOH sodium hydroxid NaOMe sodium methoxide Na₂S₂O₃sodium thiosulfate Na₂SO₄ sodium sulfate NHMDS Sodiumbis(trimethylsilyl)amide NH₄OH ammonium hydroxide (NH₄)₂CO₃ ammoniumcarbonate NH₄I ammonium iodide Na₂CO₃ sodium carbonate NaHCO₃ sodiumbicarbonate NaH sodium hydride PdCl₂dppf[1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) Pd(OH)₂palladium hydroxide Pd(PPh₃)₂Cl₂ bis(triphenylphosphine)palladium (II)dichloride Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0) PrBrpropyl bromide PBr₃ phosphorous tribromide PCC pyridinium chlorochromatePE petroleum ether PPA polyphosphoric acid PPh₃ triphenyl phosphineSelectfluor ™ 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) SOCl₂ thionyl chloride TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatographyTiCl₄ titanium chloride TMSCl trimethylsilyl chloride

Compounds of the invention can be prepared employing conventionalmethods that utilize readily available reagents and starting materials.The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. Representative compounds of thepresent invention can be prepared using the following synthetic schemes.

EXEMPLIFICATION Example I-1 Synthesis of Intermediate A—Method 1

Step 1. synthesis of 1,5-dibromo-3-methoxypentane

To a solution of 3-methoxypentane-1,5-diol (1 g, 7.46 mmol) in DCM (10mL) was added PPh₃ (5.77 g, 22.05 mmol) and CBr₄ (4.87 g, 14.7 mmol) at0° C. The mixture was stirred at 0° C. for 2 h. The mixture wasfiltrated and the filtrate was concentrated to give the residue, whichwas purified by column chromatography to give1,5-dibromo-3-methoxypentane (1.2 g, 62%). ¹H-NMR (CDCl₃): 2.0 (m, 4H),3.3 (m, 3H), 3.37 (m, 4H), 3.5 (m, 1H), 3.7 (m, 4H).

Step 2. Synthesis of6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1.037 g, 4.94 mmol) and1,5-dibromo-3-methoxypentane (1.2 g, 4.94 mmol) in THF (16 mL) was addedNaH (237.12 mg, 60%, 9.88 mmol) at room temperature. The mixture wasrefluxes for 3 h. The mixture was quenched with water and extracted withEtOAc. The organic layer was dried and concentrated to give the residue,which was purified by column chromatography to give6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (60 mg, 4%).

Example I-2 Synthesis of Intermediate A—Method 2

Step 1. Synthesis of dimethyl3,3′-(6-bromo-1-oxo-2,3-dihydro-1H-indene-2,2-diyl)dipropanoate

Under N₂, triton B (benzyl(tri-methyl)-ammonium hydroxide, 40% in MeOH,2.48 mL) was added to a solution of 6-bromo-indan-1-one (26.1 g, 0.124mol) in toluene (200 mL), and the mixture was stirred at 50° C. for 10minutes. Acrylic methyl ester (31 mL, 0.286 mol) was added at 50° C.,and the mixture was stirred at 50° C. overnight. After being cooled toroom temperature, the mixture was poured into water (150 mL), andextracted with DCM (100 mL×4). The combined organic phases were driedover Na₂SO₄, and evaporated, and purified by column chromatography onsilica gel (PE/EA=10:1) to give the compound 2 (39 g, 83%) as a yellowoil. ¹H NMR (G000044883 692-154-1A CDCl₃ 400 MHz): δ 7.75-7.81 (s, 1H),7.55-7.58 (d, 1H), 7.22-7.28 (d, 1H), 3.51-3.55 (s, 3H), 2.85-2.99 (s,2H), 2.10-2.25 (m, 4H), 1.80-1.95 (m, 4H).

Step 2. Synthesis of methyl6′-bromo-4-hydroxy-1′-oxo-1,3′-dihydrospiro[cyclohex[3]ene-1,2′-indene]-3-carboxylate

A solution of compound 2 (34 g, 88.7 mmol) in toluene (400 mL) was addeddropwise to a flask containing Na (2.24 g, 97.6 mmol) and dry toluene(100 mL) at refluxing at 120° C. The reaction mixture was heated at 120°C. for 28 hours, cooled to room temperature, and poured into a mixtureH₂O (370 mL) and 4N HCl solution (37 mL) to afford a white suspension.This mixture was extracted with AcOEt (100 mL×4), evaporated, andpurified by column chromatography on silica gel (PE/EA=10:1) to give thecompound 3 (22.11 g, 71%) as white solid. ¹H NMR: (CDCl₃ 400 MHZ): δ12.1(s, 1H), 7.82-7.85 (s, 1H), 7.61-7.65 (d, 1H), 7.22-7.25 (d, 1H),3.60-3.65 (s, 3H), 2.91-2.85 (d, 2H), 2.35-2.50 (m, 3H), 2.10-2.15 (d,1H), 1.90-2.01 (m, 1H), 1.50-1.52 (m, 1H).

Step 3. Synthesis of6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

To a suspension of compound 3 (22.1 g, 63.0 mmol) in MeOH (221 mL) wasadded a solution of NaOH (10.20 g, 0.255 mol) in H₂O (331 mL) at roomtemperature. The reaction mixture was heated at 60° C. overnight. Thesolvent was removed in vacuo, and extracted with DCM (250 mL×3). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuoto afford compound 4 (15.33 g, 83%) as a white solid, which was used forthe next step directly without purification. ¹H NMR: (CDCl₃ 400 MHz):δ7.84 (s, 1H), 7.65-7.60 (d, 1H), 7.31-7.35 (d, 1H), 3.09 (s, 2H),2.61-2.65 (m, 2H), 2.80-2.90 (m, 2H), 2.10-2.15 (m, 2H), 1.75-1.84 (m,2H).

Alternative method for synthesis of6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

To a solution of compound 1 (20 g, 95 mmol) and methyl acrylate (18 g,201 mmol) in anhydrous THF (200 mL) was added t-BuOK (16 g, 114 mmol)portionwise at room temperature. The reaction mixture was stirred atroom temperature for 1 hour. Water (400 mL) and KOH (5.32 g, 95 mmol)were added. The resulting mixture was heated to reflux overnight. 3 NHCl (150 mL) was added and extracted with CH₂Cl₂ (500 mL×2). The organiclayers were washed with NaHCO₃ (150 mL), brine (150 mL) and dried overNa₂SO₄, concentrated in vacuo to give compound A as a grey solid (23 g,83% yield), which was used for next step without purification. ¹H NMR(300 MHz, CDCl₃) δ 7.84 (s, 1H), 7.60-7.71 (d, 1H), 7.25-7.36 (d, 1H),3.11 (s, 2H), 2.60-2.71 (m, 2H), 2.35-2.46 (m, 2H), 2.10-2.23 (m, 2H),1.75-1.87 (m, 2H)

Alternative method for synthesis of6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

Step 1. 6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one

A solution of 6-bromo-2,3-dihydro-1H-inden-1-one (0.3 g, 1.36 mmol),paraformaldehyde (0.4 g, 13.6 mmol), phenylboronic acid (0.2 g, 1.64mmol) and trifluoroacetic acid (0.1 mL, 0.15 g, 1.36 mmol) in drytoluene (10 mL) was refluxed for 5 hours. When starting material wastotally consumed, the crude mixture was cooled to room temperature,neutralized with saturated aqueous Na₂CO₃, extracted with ethyl acetate,dried and concentrated under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, petroleum ether-ethylacetate, 95:5) to give compound6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (89 mg, 30%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz): 3.71 (s, 2H), 5.68 (s, 1H), 6.39 (s,1H), 7.38-7.40 (d, 1H), 7.70-7.72 (d, 1H), 7.99 (s, 1H).

Step 2. Preparation of6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

In a flame dried 20 mL vial was placed6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (98 mg, 0.441 mmol) andit was dissolved in dichloromethane (4.5 mL). To this solution was added2-trimethylsilyloxy-1,3-butadiene (98 μL, 0.565 mmol) and the solutionwas cooled down to −78° C. After stirring for 5 minutes, BF₃.OEt₂ (27mL, 0.219 mmol) was slowly added. After 5 minutes of the BF₃.OEt₂addition, TLC indicated consumption of the dienophile. The reaction wasquenched with MeOH (300 μL), allowed to stir for 5 minutes at −78° C.and then warmed up to room temperature. Once at room temperature, 2M HCl(7 mL) was added. The phases were separated and the aqueous phase wasback-extracted with dichloromethane twice (5 mL/each). The combinedorganic phases were dried over MgSO₄, filtered and concentrated underreduce pressure. The crude material was purified by flash chromatography(ISCO, 12 g SiO₂ cartridge, ethyl acetate/hexanes as the eluents). Thecorresponding fractions were combined and concentrated under reducepressure yielding 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione(62 mg, 0.212 mmol, 48% yield). ¹H NMR=(CDCl₃, 400 MHz) δ 7.68 (d, J=2.0Hz, 1H), 7.51 (dd, J=8.0, 2.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 2.94 (s,2H), 2.48 (dt, J=15.2, 5.6 Hz, 2H), 2.22 (ddd, J=15.2, 10.8, 5.6 Hz,2H), 1.98 (ddd, J=13.6, 11.2, 5.2 Hz, 2H), 1.65 (m, 2H) ppm.

Step 4. Synthesis of(trans-6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

To a 20 mL vial was added6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (102 mg, 0.349mmol) and it was dissolved in THF (3.49 mL). This solution was cooleddown to −78° C. and stirred for 5 minutes at that temperature. Then,NaBH₄ (7 mg, 0.184 mmol) were added at −78° C. After 10 minutes moreNaBH₄ (7 mg, 0.184 mmol) was added. After 5 minutes, LC/MS showed ˜70%conversion. Finally, a final portion of NaBH₄ (10 mg, 0.263 mmol) wasadded. After 5 minutes, TLC showed total consumption of the diketone.The excess NaBH₄ was quenched immediately with acetone (300 μL). Afterstirring for 15 minutes at −78° C., the reaction was warmed to roomtemperature and ethyl acetate (7 mL) and water (7 mL) were added. Thephases were separated and the aqueous phase was back-extracted withethyl acetate twice (5 mL/each). The combined organic phases were washedwith brine, dried over MgSO₄, filtered and concentrated under reducepressure. The crude material was purified by flash chromatography (ISCO,12 g SiO₂ cartridge, ethyl acetate/hexanes as the eluents). Thefractions corresponding to the isomer shown in the scheme were combinedand concentrated under reduce pressure yieldingtrans-6′-bromo-4-hydroxyspho[cyclohexane-1,2′-inden]-1′(3′H)-one (71 mg,0.241 mmol, 69% yield) as a colorless oil. M+H=294.9, 296.9; ¹HNMR=(CDCl₃, 400 MHz) δ 7.84 (bs, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.32(d, J=8.0 Hz, 1H), 3.73 (m, 1H), 2.96 (s, 2H), 2.04 (m, 2H), 1.94 (s,1H), 1.77 (m, 2H), 1.47-1.40 (m, 4H) ppm.

Step 5. Synthesis of Intermediate A:trans-6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

In a 4 mL vial was placed6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (5 mg, 0.017mmol) and acetonitrile (150 μL) was added. To this solution were addedsilver oxide (27 mgs, 0.117 mmol), freshly grinded Drierite (˜100 mgs offine white powder) and methyl iodide (48 μL, 0.769 mmol), in thatparticular order. The vial was capped and the reaction allowed stir atroom temperature overnight (˜14 hours). The next morning, LC/MSindicated total consumption of the alcohol. The reaction was filteredthru a pad of celite, and the pad was washed with ethyl acetate (4 mL).The filtrate was concentrated under reduced pressure yielding 3 mgs ofthe desired product. ¹H NMR confirms the structure as well as LC/MS.

Example 1 Synthesis of Compound 1

Step 1: Synthesis of6′-bromo-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-1′-amine(1b)

To a solution of compound A (0.51 g, 1.73 mmol) in MeOH (5 mL) was addedNH₄OAc (1.33 g, 17.3 mmol) and NaBH₃CN (0.13 g, 2.1 mmol) at roomtemperature. After addition, the mixture was stirred in microwave at110° C. for 90 min. TLC showed that the reaction was completed. Thereaction mixture was concentrated in vacuo to give the residue, whichwas dissolved in ethyl acetate (25 mL) and washed with 2 N HCl (10 mL),aqueous was added 2 N NaOH (12 mL) and was extracted with ethyl acetate(25 mL×2) to give compound 1a (0.28 g, 52%) as a white solid.

¹H NMR (CDCl₃ 400 MHz): δ 7.35 (s, 1H), 7.21-7.27 (m, 1H), 6.96-6.98 (d,J=7.6 Hz, 1H), 3.83 (s, 1H), 3.29 (s, 3H), 3.04-3.11 (m, 1H), 2.81-2.85(m, 1H), 2.44-2.48 (m, 1H), 1.86-1.98 (m, 2H), 1.53-1.56 (m, 2H),1.23-1.32 (m, 2H), 1.16-1.21 (m, 2H).

Step 2: Synthesis of6′-bromo-1′-isothiocyanato-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene](1b)

A mixture of compound 1a (0.28 g, 0.9 mmol) in methylene chloride (10mL) and saturated aqueous sodium bicarbonate (10 mL) was cooled with anice bath, treated with thiophosgene (0.12 g, 1.0 mmol), stirredvigorously for 30 min, TLC showed that the reaction was completed,diluted with methylene chloride (30 mL). The phases were separated. Theorganic phase was washed with brine (30 mL), dried over sodium sulfateand concentrated to dryness to give compound 1b (0.25 g, 79%) as a whiteoil, which was used directly for the next step without purification.

Step 3: Synthesis of(E)-N-(5′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(1c)

A mixture of potassium t-butoxide (84.5 mg, 0.78 mmol) in THF (5 mL) at−78° C. was slowly added over a period of 2 min to a solution ofcompound 1b (0.25 g, 0.71 mmol) and carbon disulfide (81 mg, 1.065 mmol)in THF (5 mL). After addition, the reaction mixture was stirred at −78°C. for 0.5 h, then slowly warmed to room temperature and stirred for 1h. The reaction mixture was partitioned between with methylene chloride(20 mL) and water (20 mL). The phases were separated. The organic phasewas washed with brine (15 mL), dried over sodium sulfate andconcentrated to dryness to give compound 1c (0.25 g, 82%) as a whitesolid, which was used directly for the next step without purification.

Step 4: Synthesis of(E)-N-(5′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(1d)

A mixture of compound 1c (140 mg, 0.33 mmol), compound 1A (146 mg, 0.98mmol) and triethylamine (217 mg, 2.15 mmol) in ethanol (10 mL) wasstirred at ice bath temperature for 2 h, warmed to room temperature,stirred at room temperature for 24 h and heated to 70° C. for 2 h. Aftercooling to room temperature, the solution was concentrated under reducedpressure. The residue was partitioned between EtOAc and water, theorganic phase was washed sequentially with 1 N aq. HCl and brine (10mL), dried over Na₂SO₄ and concentrated under reduced pressure to givecompound 1d (80 mg, 56%) as a white solid, which was purified bypreparative TLC (hexanes:EtOAc=5:1).

Step 5: synthesis of(E)-N-(5′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(1e)

A mixture of compound 1d (80 mg, 0.18 mmol) and t-butyl hydroperoxide(508 mg of a 65% solution in water, 3.6 mmol) in methanol (10 mL) andconcentrated aqueous ammonium hydroxide (2 mL) was stirred at roomtemperature overnight. The reaction mixture was treated with 10% aqueoussodium thiosulfate (8 mL) and concentrated under reduced pressure toremove most of the methanol. The resulting aqueous mixture was extractedwith methylene chloride (20 mL×2). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and concentrated todryness. Purification of this residue by pre-TLC afforded compound 1e(40 mg, 52%) as a white solid.

Step 6: Synthesis of Compound 1

Compound 1e (20 mg, 0.048 mmol) under a nitrogen atmosphere was treatedsequentially with compound 1B (16.6 mg, 0.096 mmol) in 1,4-dioxane (2mL), Cs₂CO₃ (2 M, 0.072 mL) and Pd(PPh₃)₂Cl₂ (5 mg). The mixture washeated to reflux for 15 min. TLC showed that the reaction was completed.The reaction mixture was concentrated in vacuo to give the residue,which was purified by pre-TLC and pre-HPLC to give compound 1 (1.9 mg,yield 8.6%) as a white solid.

¹H NMR (CD₃OD 400 MHz): δ 7.40-7.43 (dd, J=1.2, 4.0 Hz, 1H), 7.34 (s,1H), 7.25-7.27 (d, J=7.6 Hz, 1H), 7.17-7.21 (m, 2H), 7.03-7.05 (m, 1H),3.63-3.82 (m, 4H), 3.38 (s, 3H), 2.90-3.07 (m, 3H), 1.83-1.93 (m, 3H),1.53-1.59 (m, 1H), 1.15-1.30 (m, 4H).

LC-MS t_(R)=1.015 min in 2 min chromatography, MS (ESI) m/z 469 [M+H]⁺

Example 2 Synthesis of Compound 2

Starting with intermediate 1e (10 mg, 0.048 mmol) from Example 1,compound 1e was reacted with 3-triluoromthoxy phenylboronate asdescribed in step 6 of example 1. The crude product was purified bypreparative TLC (CH₂Cl₂:MeOH=10:1) and HPLC to give compound 2 (1.6 mg,6.7%) as a white solid.

¹H NMR (CD₃OD 400 MHz): δ 7.47-7.49 (d, J=7.6 Hz, 1H), 7.35-7.42 (m,3H), 7.26-7.27 (d, J=7.6 Hz, 1H), 7.12-7.18 (m, 2H), 3.65-3.82 (m, 4H),3.25 (s, 3H), 2.90-3.07 (m, 3H), 1.85-1.95 (m, 3H), 1.52-1.59 (m, 1H),1.20-1.32 (m, 4H).

LC-MS t_(R)=1.035 min in 2 min chromatography, MS (ESI) m/z 501 [M+H]⁺

Example 3 Synthesis of Compound 3

This was synthesized as described in Example 1, step 4.1,3-propylenediamine was utilized instead ofO-(2-aminoethyl)hydroxylamine and was further elaborated as in Example 1to give final compound that was purified by pre-TLC (CH₂Cl₂:MeOH=5:1)and pre-HPLC to give compound 3 (97.3 mg) as a white solid.

LC-MS t_(R)=1.102 min in 2 min chromatography, MS (ESI) m/z 467.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.45-7.48 (d, J=8.0 Hz, 1H), 7.38 (s, 1H),7.31-7.33 (d, J=7.6 Hz, 1H), 7.22-7.26 (d, J=8.0 Hz, 1H), 7.20 (s, 1H),7.07-7.11 (d, J=8.4 Hz, 1H), 3.55-3.58 (m, 2H), 3.27 (s, 3H), 3.19-3.23(m, 1H), 3.00-3.09 (m, 4H), 1.91-2.00 (m, 3H), 1.74-1.76 (m, 2H),1.58-1.59 (m, 1H), 1.24-1.35 (m, 4H).

Example 4 Synthesis of Compound 4

The intermediate 3b from Example 3 (50 mg, 0.12 mmol) was dissolved inEt₃N (5 mL) and Et₂NH (1 mL), the resulting mixture was degassed andpurged with N₂ for three times. PdCl₂(PPh₃)₂ (5 mg) and CuI (4 mg) wereadded under nitrogen and the system was degassed again.Ethynylcyclopropane (0.5 mL, excess) was added by syringe. The systemwas degassed one more time. The reaction was heated to 50˜60° C. for 12h. LCMS showed that the reaction was completed; the solvent was removedunder reduced pressure. The residue was partitioned by CH₂Cl₂ (10 mL)and water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (2×10mL), the combined organic layers were washed with brine (2×10 mL), driedover anhydrous Na₂SO₄ and concentrated to dryness. Purification of thisresidue by preparative TLC (CH₂Cl₂:MeOH=5:1) and pre-HPLC to affordedcompound 4 (3.5 mg, 7%) as a white solid.

LC-MS t_(R)=1.041 min in 2 min chromatography, MS (ESI) m/z 403.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.19-7.24 (q, 2H), 7.00 (s, 1H), 3.61-3.66 (m,2H), 3.35 (s, 3H), 3.23-3.28 (m, 2H), 3.14-3.15 (m, 1H), 2.97-3.02 (m,2H), 1.96-2.04 (m, 3H), 1.80-1.83 (m, 2H), 1.57-1.58 (m, 1H), 1.19-1.45(m, 5H), 0.84-0.88 (m, 2H), 0.68-0.71 (m, 2H).

Example 5 Synthesis of Compound 5

This was synthesized by method described in Example 2. 3-pyridylboronatewas utilized instead of trifluromethoxy phenylboroante. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=5:1) andpreparative HPLC to afford product compound 5 (3.2 mg, 8%) as a whitesolid.

LC-MS t_(R)=1.178 min in 2 min chromatography, MS (ESI) m/z 416.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.76 (s, 1H), 8.49-8.51 (d, J=4.8 Hz, 1H),8.06-8.09 (dd, J=8.0 Hz, 1H), 7.57-7.59 (d, J=8.0 Hz, 1H), 7.49-7.53(t_(R) J=8.0 Hz, 1H), 7.42-7.44 (d, J=7.6 Hz, 1H), 7.33 (s, 1H),3.63-3.68 (m, 2H), 3.38 (s, 3H), 3.05-3.29 (m, 5H), 1.99-2.07 (m, 3H),1.81-1.85 (m, 2H), 1.63-1.66 (t, J=12.0 Hz, 1H), 1.30-1.43 (m, 4H).

Example 6 Synthesis of Compound 6

As described in example 1, in step 4, 3,3-difluoro-1,3 propylenediaminewas utilized instead of O-(2-aminoethyl)hydroxylamine and was furtherelaborated as in example 1 to yield product (0.35 g) as a white solid.

LC-MS t_(R)=1.188 min in 2 min chromatography, MS (ESI) m/z 503.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.42-7.44 (d, J=7.6 Hz, 1H), 7.33 (s, 1H),7.27-7.29 (d, J=8.0 Hz, 1H), 7.18-7.21 (d, J=8.4 Hz, 2H), 7.04-7.07 (d,J=10.8 Hz, 1H), 3.79-3.86 (m, 2H), 3.29-3.57 (m, 2H), 3.25 (s, 3H),2.93-3.07 (m, 3H), 1.87-1.94 (m, 3H), 1.50-1.54 (t, J=15.2 Hz, 1H),1.17-1.34 (m, 4H).

Example 7 Synthesis of Compound 7

As described in example 1, step 4,2,2-dimethylpropane-1,3-diamine wasutilized instead of O-(2-aminoethyl)hydroxylamine and was furtherelaborated to yield example 5 as a white solid.

LC-MS t_(R)=1.156 min in 2 min chromatography, MS (ESI) m/z 495.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.45-7.47 (d, J=7.6 Hz, 1H), 7.33-7.38 (t,J=10.0 Hz, 2H), 7.16-7.24 (m, 2H), 7.05-7.07 (d, J=8.4 Hz, 1H), 3.26 (s,3H), 3.07-3.15 (m, 3H), 2.95-3.04 (m, 4H), 1.84-1.94 (m, 2H), 1.74-1.79(m, 1H), 1.54-1.60 (t, J=11.6 Hz, 1H), 1.14-1.33 (m, 4H), 0.94 (s, 6H).

Example 8 Synthesis of Compound 8

Step 1 Synthesis of 2-Ethylmalononitrile

To a round bottle flask was added compound 8a (15 g, 227 mmmol),tetrabutylammonium bromide (2.9 g, 9 mmol) and ethyl idodide (17.7 g,113 mmol). The reaction mixture was stirred at 20° C. for 30 min andthen cooled to 0° C. K₂CO₃ (15.6 g, 113 mmol) was added slowly to themixture. The reaction mixture was then warmed up to 20° C. and keptstirring for 30 min. The mixture was partitioned between water (300 mL)and CH₂Cl₂ (400 mL). The organic fractions were collected, dried overMgSO₄ and concentrated under reduced pressure and the residue waspurified by column chromatography on silica gel eluting with 10% EtOAcin hexane to afford compound 8b (5.9 g, 28%) as a yellow oil.

¹HNMR (DMSO-d₆, 400 MHz) δ 4.72-4.77 (m, 1H), 1.94-1.98 (m, 2H),1.04-1.09 (m, 3H).

Step 2 Synthesis of tert-butyl 2-ethylpropane-1,3-diyldicarbamate

A round bottom flask was charged with compound 8b (5.0 g, 53 mmol),(Boc)₂O (35 g, 160 mmol), Ranney Ni (5 g) and CH₃OH (80 mL). Thereaction mixture was stirred at room temperature under H₂ atmosphere (1atm) overnight. The mixture was filtrated and the filtrate wasconcentrated under vacuum. The residue was purified by column (petroleumether:ethyl acetate=2:1) to give compound 8c (3.4 g, 22%) as a yellowoil, which was used directly for the next step without furtherpurification.

Step 3: Synthesis of 2-ethylpropane-1,3-diamine as bis TFA salt

To a round bottle was dissolved compound 8c (0.5 g, 1.65 mmol) in amixture of CH₂Cl₂ and TFA (10 mL, CH₂Cl₂:TFA=4:1). The reaction mixturewas stirred at 20° C. for 30 min. The reaction solvent was removed undervacuum to afford crude compound 8d (0.34 g, crude) as a yellow oil,which was used for the next step directly without further purification.

¹HNMR (CD₃OD, 300 MHz) δ 3.00-3.06 (m, 3H), 2.04 (m, 1H), 1.54-1.58 (m,2H), 1.00-1.04 (m, 3H).

This was further elaborated as described in example 1. As described inexample 1, in step 4,2-ethylpropane-1,3-diamine was utilized instead ofO-(2-aminoethyl)hydroxylamine and was further elaborated to yieldcompound 8 (89 mg) as a white solid.

LC-MS t_(R)=1.198 min in 2 min chromatography, MS (ESI) m/z 495.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.53-7.55 (d, J=8.0 Hz, 1H), 7.41-7.43 (d,J=7.6 Hz, 2H), 7.34-7.36 (d, J=8.0 Hz, 1H), 7.25-7.27 (d, J=7.6 Hz, 1H),7.04-7.08 (d, J=8.0 Hz, 1H), 3.86-3.92 (m, 0.7H), 3.37-3.44 (m, 0.3H),3.26-3.92 (s, 2H), 3.01-3.09 (m, 5H), 2.56 (s, 2H), 1.90-2.02 (m, 3H),1.61-1.68 (m, 1H), 1.17-1.40 (m, 7H), 0.89-0.93 (t, J=7.2 Hz, 3H).

Example 9 Synthesis of Compound 9

Step 1: Procedure for Preparation of Compound 9b

To a solution of NH₃/MeOH (sat., 50 mL) was added compound 9a (5 g, 25.5mmol) at −78° C. and stirred at this temperature for 2 h. Then thereaction mixture was allowed to warm to room temperature slowly andstirred overnight. The reaction mixture was concentrated under reducedpressure to dryness to give compound 9b (3.3 g, 94%) as a white solid.

¹H NMR (DMSO-d₆ 400 MHz): δ 8.24 (br, 2H), 8.09 (br, 2H).

Step 2: Procedure for Preparation of Compound 9c

To a solution of BH₃-THF (1 M in THF, 101.5 mL, 101.5 mmol) was addedslowly compound 9b (2.8 g, 20.3 mmol) at ˜0° C. cooled under an icebath. The resulting mixture was stirred at this temperature till thereaction mixture turned clear. Then the solution was heated at refluxovernight. The mixture was cooled under an ice bath and MeOH (100 mL)was added dropwise. The resulting solution was concentrated to drynessand another 30 mL of MeOH was added. The solvent was removed again. Thisprocess was repeated for 3 times. Then to the residue was added asolution of HCl/MeOH (4 N, 30 mL) slowly and a lot of white solid wasprecipitated. The solid was collected by filtration and washed with EtOH(5 mL), dried under reduced pressure to give compound 9c (1.59 g, 43%)as a white HCl salt.

¹H NMR (DMSO-d₆, 400 MHz): δ 8.83 (br, 6H), 3.61 (t, J=31.2 Hz, 4H).

Step 3: Procedure for Preparation of Compound 9e

Compound 9d (3.6 g, 11.6 mmol) was dissolved in Et₃N (50 mL) and Et₂NH(10 mL), the resulting mixture was degassed and purged with N₂ for threetimes. Pd(PPh₃)₂Cl₂ (400 mg) and CuI (120 mg) were added under anitrogen atmosphere atmosphere and the system was degassed again.Ethynylcyclopropane (6 mL, excess) was added by syringe. The system wasdegassed one more time. The reaction was heated at 50-60° C. for 12 h.LCMS showed that the reaction was completed; solvent was removed underreduced pressure. The residue was partitioned by CH₂Cl₂ (100 mL) andwater (100 mL). The aqueous layer was extracted by CH₂Cl₂ (2×100 mL),the combined organic layers were washed with brine (2×100 mL), driedover Na₂SO₄ and concentrated to dryness. Purification of this residue bycolumn chromatography (petroleum ether:ethyl acetate=50:1 to 5:1)afforded compound 9e (3.45 mg, 100%) as a white solid.

Compound 9e was further elaborated as described in example 1 from step1-5 to yield Compound 9 as a white solid.

LC-MS t_(R)=1.120 min in 2 min chromatography, MS (ESI) m/z 439.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.22-7.29 (q, J=8.4 Hz, 2H), 7.11 (s, 1H),3.96-4.05 (m, 2H), 3.62-3.76 (m, 2H), 3.36 (s, 3H), 3.19-3.25 (m, 1H),3.06 (s, 2H), 1.96-2.06 (m, 3H), 1.39-1.53 (m, 6H), 0.85-0.90 (m, 1H),0.68-0.72 (m, 2H).

The crude product was purified by preparative TLC (CH₂Cl₂:MeOH=5:1) andpreparative HPLC to afford product compound 9 (1.5 mg, 8%) as a whitesolid.

LC-MS t_(R)=0.876 min in 2 min chromatography, MS (ESI) m/z 452.2[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.76 (s, 1H), 8.51 (s, 1H), 8.06-8.08 (d,J=7.6 Hz, 1H), 7.59-7.61 (d, J=9.2 Hz, 1H), 7.50-7.53 (t, J=8.0 Hz, 1H),7.43-7.45 (d, J=7.6 Hz, 1H), 7.36 (s, 1H), 3.92-4.00 (m, 2H), 3.50-3.70(m, 2H), 3.37 (s, 3H), 3.07-3.27 (m, 3H), 1.96-2.07 (m, 3H), 1.62-1.65(t, 1H), 1.29-1.48 (m, 4H).

Example 10 Synthesis of Compound 10

This was synthesized by procedure described in example 9. Starting withIntermediate 9h from example 9, it was further elaborated as describedin example 6 utilizing 1,1-bis(aminomethyl)cyclopropane.

The crude product was purified by preparative HPLC (acid) to giveproduct compound 10 (0.6 mg, 1%) as a white solid (trifluroacetic salt).

LC-MS t_(R)=0.948 min in 2 min chromatography, MS (ESI) m/z 428.3[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.24 (m, 2H), 7.13 (s, 1H), 3.9 (s, 3H),3.57-3.38 (m, 3H), 3.03 (m, 3H), 2.0-1.7 (m, 2H), 1.48-1.19 (m, 8H),0.7-0.6 (m, 13H).

Example 11 Synthesis of Compound 11

This was synthesized by procedure described in example 3 forintermediate 3b. Starting with intermediate 1, it was further elaboratedas described in example 7 utilizing 1,1-bis(aminomethyl)cyclopropane.

The crude product was purified by preparative TLC (CH₂Cl₂:MeOH=5:1) andpreparative HPLC (basic) gave compound 11 (15 mg, 31%) as a white solid.

LC-MS t_(R)=1.028 min in 2 min chromatography, MS (ESI) m/z 443.1, 445.1[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.42-7.45 (d, J=8.0 Hz, 1H), 7.29 (s, 1H),7.23-7.29 (d, J=8.0 Hz, 1H), 3.63-3.66 (d, J=11.6 Hz, 1H), 3.39 (s, 3H),3.10-3.19 (m, 1H), 2.98-3.03 (m, 3H), 1.96-2.07 (m, 3H), 1.55-1.62 (m,1H), 1.25-1.45 (m, 6H), 0.53-0.72 (m, 4H).

Example 12 Synthesis of Compound 12

Procedure for Preparation of Compound 2

To a solution of compound 1 (5.0 g, 19 mol) in anhydrous THF (50 mL) wasadded tert-butylsulfanilamide (4.6 g, 38 mol) and Ti(OEt)₄ (22 g, 76.9mol). The solution was heated at reflux for 48 h under a N₂ atmosphere.Water (10 mL) was added to quench the reaction and the mixture wasextracted with EtOAc (2×50 mL). The combined organic layers were driedover Na₂SO₄ and evaporated under vacuum to give the crude. The crude waspurified by chromatographic on silica gel (hexane:EtOAc=20:1) to affordcompound 2 (3.0 g, 43%) as a yellow solid.

Procedure for Preparation of Compound 3

To a mixture of compound 2 (200 mg, 0.55 mmol) in anhydrous THF (3 mL)was added dropwise n-BuLi (0.44 mL, 1.10 mmol) at −78° C. under a N₂atmosphere. After stirring for 10 min, a solution of3-Bromo-5-trifluoromethyl-pyridine (246 mg, 1.10 mmol) in anhydrous THF(2 mL) was added. The solution was stirred at −78° C. for 30 min, andthen warmed to room temperature. Sat. NH₄Cl (2 mL) solution was added toquench the reaction and then extracted with EtOAc (3×5 mL). The combinedorganic layers were dried over Na₂SO₄ and evaporated under vacuum toafford the crude product. The crude was purified by preparative TLC(EtOAc) to give compound 3 (70 mg, 25%) as a white solid.

Procedure for Preparation of Compound 4

A solution of compound 3 (50 mg, 0.137 mmol) in sat. HCl:MeOH (5 mL) wasstirred at room temperature overnight. The reaction solution wasevaporated under vacuum at room temperature. The residue was dissolvedin MeOH and NH₃.H₂O was added to adjust pH=8-9, then was evaporated. Theresidue was washed with CH₂Cl₂ (5 mL) and the solid was filtered off.The filtrate was evaporated to give compound 4 (20 mg, 36%) as a whitesolid.

Procedure for Preparation of Compound 5

To a solution of compound 4 (20 mg, 0.057 mmol) in MeOH (10 mL) wasadded PtO₂ (5 mg) (the mixture was added drops of HCl/MeOH). The mixturewas stirred at room temperature under a H₂ (30 Psi) atmosphereovernight. The reaction mixture was adjust to pH=8 with NH₃.H₂O, andevaporated under vacuum. The residue was dissolved in EtOAc (10 mL), andthe solid was filtered off. The filtrate was evaporated to give crudecompound 5 (20 mg, crude). The crude was used in the next step withoutfurther purification.

Procedure for Preparation of Compound 12

To a solution of compound 5 (20 mg, 0.049 mmol) in ethanol (3 mL) wasadded BrCN (10 mg). The solution was heated at 80° C. for 30 min in amicrowave reactor. Then the solvent was evaporated under vacuum and theresidue was purified by preparative HPLC to afford compound 12 (1.1 mg,5%) as a white solid.

LC-MS t_(R)=1.494 min in 2 min chromatography, MS (ESI) m/z 438 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.21 (m, 1H), 6.94 (m, 1H), 6.64 (s, 1H), 4.29(d, J=7.6 Hz, 1H), 3.80 (m, 3H), 3.38 (s, 3H), 3.01-3.11 (m, 2H),2.62-2.76 (m, 2H), 2.00-2.19 (m, 4H), 1.65-1.74 (m, 4H), 1.33-1.49 (m,5H).

Example 13 Synthesis of Compound 13

Procedure for Preparation of Compound 2

To a solution of compound 1 (200 mg, 0.67 mmol) in THF (4 mL) was addedTi(OEt)₄ (2 mL, 6.7 mmol). After being stirred at room temperature for 1h, tert-butylsulfinamide (300 mg, 2.68 mmol) was added. The reactionmixture was stirred at reflux overnight. Then the mixture waspartitioned between H₂O (10 mL) and EtOAc (20 mL). The mixture wasfiltered and the filtrate was extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄ and concentrated to dryness. The residue was purified bychromatography (petroleum ether:ethyl acetate=10:1) to give compound 3(250 mg, 87%) as a yellow solid.

Procedure for Preparation of Compound 13

To a solution of i-PrMgCl—LiCl (4.83 mL, 6.28 mmol) was added compound2A (1.44 g, 6.28 mmol) in THF (2 mL) at −20° C. in one portion, and themixture was stirred at −20° C. for 20 min. Then to the above mixture wasadded the solution of compound 2 (250 mg, 0.628 mmol) in THF (1 mL)slowly at −20° C., followed by CuCN—LiCl solution (0.002 mL, 1 M in THF)and the mixture was stirred for 3 h at same temperature. The reactionwas quenched by addition of saturated aqueous NH₄Cl (3 mL). The aqueouslayer was extracted with EtOAc (3×20 mL), the combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄ and concentrated togive the residue, which was purified by preparative TLC(CH₂Cl₂:MeOH=10:1) and HPLC (basic) to give compound 13 (2.0 mg, 11%).

LC-MS t_(R)=1.087 min in 2 min chromatography, MS (ESI) m/z 411/413[M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.16 (d, J=8.0 Hz, 1H), 7.65-7.76 (m, 2H),7.04-7.53 (m, 3H), 7.03 (s, 1H), 3.21 (s, 3H), 3.08 (m, 1H), 1.92-2.05(m, 2H), 1.69-1.74 (m, 1H), 1.40-1.52 (m, 3H), 1.27-1.32 (m, 2H),0.90-1.05 (m, 2H)

Example 14 Synthesis of Compound 14

A solution containing compound 1A (0.2 mL, excess) and compound 1 (20mg, 0.046 mol) in toluene (2 mL) was deoxygenated by bubbling a streamof nitrogen through the reaction mixture for 5 min. Then, PdCl₂(PPh₃)₂(5 mg) was added. The reaction vial was sealed and placed into CEMmicrowave reactor and irradiated at 150° C. for 35 min. After beingcooled to room temperature, the mixture was partitioned between EtOAc(20 mL) and aqueous CsF (4 M, 20 mL), and the aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (15 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by preparative TLC(CH₂Cl₂:MeOH=10:1) and HPLC (basic) to yield compound 14 (3.3 mg, 18%)as a white solid.

LC-MS t_(R)=1.076 min in 2 min chromatography, MS (ESI) m/z 397 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.04 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz,1H), 7.57 (t, J=7.6 Hz, 1H), 7.21-7.30 (m, 3H), 6.67 (s, 1H), 3.33 (s,3H), 2.97 (m, 1H), 1.82-1.93 (m, 2H), 1.60-1.63 (m, 1H), 1.19-1.37 (m,5H), 0.92-0.93 (m, 1H), 0.70-0.74 (m, 2H), 0.54-0.56 (m, 2H)

Example 15 Synthesis of Compound 15

Pd(PPh₃)₂Cl₂ (5 mg) in a 10 mL of flask was treated with compound 1 (40mg, 0.078 mmol), 1,4-dioxane (3 mL), compound 1A (17 mg, 0.118 mmol) andCs₂CO₃ (2 N, 0.52 mL) sequentially under N₂. The mixture was heatedunder 120° C. under N₂ in a CEM microwave reactor for 15 min. Thereaction mixture was concentrated in vacuo to give the residue, whichwas purified by preparative TLC on silica gel (CH₂Cl₂:MeOH=10:1) and byHPLC (0.1% TFA as buffer) to give compound 15 (1.0 mg, 5%) as a whitesolid.

LC-MS (698-146-1A): t_(R)=1.005 min in 2 min chromatography, MS (ESI)m/z 434 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.17 (d, J=7.6 Hz, 1H), 7.89 (m, 1H), 7.82 (m,1H), 7.68 (m, 5H), 7.40 (d, J=7.6 Hz, 1H), 7.18 (s, 1H), 3.41 (m, 2H),3.39 (s, 3H), 3.15 (m, 1H), 2.07 (m, 1H), 1.96 (m, 1H), 1.78 (m, 1H),1.51 (m, 3H), 1.34 (m, 2H), 1.05 (m, 1H).

Example 16 Synthesis of Compound 16

This was synthesized by method described in example 15. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) and HPLC togive compound 16 (5.0 mg, 13%) as a white solid.

LC-MS t_(R)=1.034 min in 2 min chromatography, MS (ESI) ink 478 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.97 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H),7.17-7.18 (d, J=7.6 Hz, 1H), 7.65-7.79 (m, 4H), 7.40 (d, J=7.6 Hz, 1H),7.32 (s, 1H) 3.23-3.33 (m, 2H), 3.20 (s, 3H), 3.00-3.11 (m, 1H),1.86-1.98 (m, 2H), 1.59-1.62 (m, 1H), 1.30-1.40 (m, 3H), 1.15-1.29 (m,1H), 0.92-1.01 (m, 1H).

¹⁹F-NMR (CD₃OD 400 MHz): δ −63.96.

Example 17 Synthesis of Compounds 17, 18 and 19

Procedure for Preparation of Compound 2

To a solution of compound 1A (5.31 g, 37.5 mmol) in THF (120 mL) wasadded MeLi (12.5 mL, 37.5 mmol) at 0° C. under a nitrogen atmosphere andthe resulting mixture was stirred at 0° C. for 1 h. After being cooledto −78° C., a solution of compound 1(4 g, 31.2 mmol) in THF (200 mL) wasadded dropwise slowly. The dark solution was stirred at −78° C. for 40min, and a solution of I₂(9.56 g, 37.5 mmol) in THF (50 mL) was added toabove solution. After being stirred at −78° C. for 2 h, the mixture wasallowed to warm to room temperature and stirred overnight. Then themixture was quenched by addition of saturated aqueous NH₄Cl (10 mL). Theaqueous layer was extracted with EtOAc (3×200 mL), and the combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo to givethe crude product, which was purified by column chromatography on silicagel (petroleum ether:ethyl acetate=10:1) and HPLC to give compound 2(1.5 g, 19%) as a yellow solid.

¹H NMR (CD₃OD 400 MHz): δ 8.43 (s, 1H), 7.87-7.94 (m, 2H).

Procedure for Preparation of Compound 5

To a solution of compound 2 (500 mg, 0.198 mmol) in THF (2 mL) was addedn-BuLi (0.08 mL, 0.198 mmol) at −78° C., and the mixture was stirred at−78° C. for 30 min. Then to the above mixture was added the solution ofcompound 4 (81 mg, 0.198 mmol) in THF (1 mL) at −78° C. slowly, and themixture was stirred at −78° C. for additional 2 h. The reaction mixturewas allowed to warm to the room temperature and stirred overnight. Thenthe mixture was quenched by addition of saturated aqueous NH₄Cl (3 mL).The aqueous layer was extracted with EtOAc (3×20 mL), and the combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo to givethe residue, which was purified by preparative TLC (CH₂Cl₂:MeOH=15:1)and HPLC to give compound 5 (14 mg, 16%) as a yellow solid.

Procedure for Preparation of Compound 6

To a solution of compound 5 (14 mg, 0.032 mmol) in THF (1 mL) was addedDMAP (6 mg, 0.048 mmol), (Boc)₂O (11 mg, 0.048 mmol) and Et₃N (6.4 mg,0.064 mmol) at room temperature and the resulting mixture was stirredovernight. The solvent was removed in vacuo to yield the crude compound,which was purified by preparative TLC (petroleum ether:ethylacetate=3:1) to give compound 6 (9 mg, 52%) as a white solid.

Procedure for Preparation of Compound 7

An oven dried three-necked round bottom flask equipped with condenserwas charged with compound 6 (24 mg, 0.046 mmol), Et₃N (2.5 mL) and Et₂NH(0.5 mL) under a nitrogen atmosphere. To this solution was added CuI(0.44 mg, 0.0023 mmol) and PdCl₂(PPh₃)₂ (2 mg, 0.0023 mmol). The systemwas degassed once again, then cyclopropyl acetylene (0.5 mL, excess) wasadded and the mixture was stirred at 60° C. (oil bath) overnight. Thesolvent was evaporated in vacuo and the residue was partitioned betweenethyl acetate (20 mL) and water (10 mL). The aqueous layer was extractedwith ethyl acetate (2×30 mL), the combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, and concentrated under reducedpressure to dryness. The crude product was purified by preparative TLC(petroleum ether:ethyl acetate=3:1) to give compound 7 (7 mg, 30%) as awhite solid.

Procedure for Preparation of Compound 17

A solution of compound 7 (7 mg, 0.0134 mmol) in dioxane (2 mL) wasplaced into CEM microwave reactor and irradiated at 120° C. for 15 min.The solvent was removed by evaporation in vacuo to yield the crudecompound, which was purified by HPLC (basic) to give compound 17 (4.4mg, 52%) as a white solid.

LC-MS t_(R)=1.158 min in 2 min chromatography, MS (ESI) m/z 422 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 7.87 (d, J=8.0 Hz, 1H), 7.73 (dd, J=0.8, 7.6Hz, 1H), 7.42 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.13 (dd, J=1.6, 8.0 Hz,1H), 6.50 (s, 1H), 3.33 (s, 3H), 3.23-3.33 (m, 2H), 2.88-3.00 (m, 1H),1.79-1.95 (m, 2H), 1.51-1.62 (m, 1H), 1.32-1.48 (m, 1H), 1.10-1.38 (m,4H), 0.75-0.88 (m, 1H), 0.65-0.75 (m, 2H), 0.50-0.55 (m, 2H).

Chiral Separation of Compound 17: Preparation of Compounds 18 and 19

Compound 17 (50 mg, 0.12 mmol) was re-purified by preparative SFC togive compound 19 (18.30 mg, 37%) and compound 18 (6.70 mg, 13%). Spectrafor compound 19:

LC-MS t_(R)=0.930 min in 2 min chromatography, m/z 422 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.32 (d, J=8.4 Hz, 1H), 8.03 (d, J=7.2 Hz,1H), 7.77 (s, 1H), 7.40 (dd, J=1.2, 6.8 Hz, 2H), 6.88 (s, 1H), 3.33 (s,3H), 3.25-3.28 (s, 2H), 3.10 (m, 1H), 1.95-2.07 (m, 2H), 1.74-1.76 (m,1H), 1.33-1.49 (m, 5H), 1.05-1.06 (m, 1H), 0.81-0.86 (m, 2H), 0.66-0.67(m, 2H).

SFC: t_(R)=7.67 min in 15 min chromatography, ee=98%.

Spectra for Compound 18:

LC-MS t_(R)=0.930 min in 2 min chromatography, m/z 422 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.32 (d, J=8.4 Hz, 1H), 8.03 (d, J=7.2 Hz,1H), 7.77 (s, 1H), 7.40 (dd, J=1.2 Hz, 6.8, 2H), 6.88 (s, 1H), 3.33 (s,3H), 3.25-3.28 (s, 2H), 3.10 (m, 1H), 1.95-2.07 (m, 2H), 1.74-1.76 (m,1H), 1.33-1.49 (m, 5H), 1.05-1.06 (m, 1H), 0.81-0.86 (m, 2H), 0.66-0.67(m, 2H).

SFC: t_(R)=8.29 min in 15 min chromatography, ee=90%.

Example 18 Synthesis of Compound 20

This was synthesized by method described in example 15. The solution wasconcentrated in vacuo and the residue was purified by preparative TLC(CH₂Cl₂:MeOH=10:1) and HPLC to give compound 20 (1.6 mg, 4%) as a whitesolid.

LC-MS t_(R)=0.994 min in 2 min chromatography, MS (ESI) m/z 486 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.34 (d, J=8.4 Hz, 1H), 8.05 (d, J=8.0 Hz,1H), 7.81 (s, 1H), 7.72 (d, J=9.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.42(s, 1H), 7.26-7.29 (m, 1H), 7.17 (d, J=8.4 Hz, 1H), 3.23-3.33 (m, 2H),3.20 (s, 3H), 3.00-3.11 (m, 1H), 1.86-1.98 (m, 2H), 1.59-1.62 (m, 1H),1.30-1.40 (m, 3H), 1.15-1.29 (m, 1H), 0.92-1.01 (m, 1H).

Example 19 Synthesis of Compound 21

Step 1. Synthesis of2-(5-bromo-2-fluorophenyl)-2-(trimethylsilyloxy)acetonitrile

To a solution of 5-bromo-2-fluorobenzaldehyde (3.4160 g, 16.8 mmol) andDMAP (0.0256 g, 0.21 mmol, 0.012 equiv) in CH₃CN (35 mL) was added TMSCN(1.8885 g, 19.0 mmol, 1.13 equiv) dropwise via a syringe under nitrogenat room temperature. After 3.75 h, the solvent was removed under reducedpressure. The crude product was directly used in the next step withoutfurther purification.

Step 2. Synthesis of 4-(5-bromo-2-fluorobenzoyl)-4-hydroxycyclohexanone

To a solution of2-(5-bromo-2-fluorophenyl)-2-(trimethylsilyloxy)acetonitrile (16.8mmol), obtained as described above, in THF (10 mL) was added LiHMDS (1.0M in THF, 18 mL, 18 mmol, 1.07 equiv) via a syringe under nitrogen at−78° C. After 1.25 h, a solution of 1,4-cyclohexanedione mono-ethyleneketal (2.6310 g, 16.8 mmol, 1.0 equiv) in THF (20 mL) was added dropwisevia a cannula. The resulting mixture was allowed to slowly warm to 10°C. over 16 h. The mixture was then quenched with saturated NH₄Cl (10 mL)and H₂O (10 mL), extracted twice with ethyl acetate, and dried overNa₂SO₄. After the solvent was evaporated under reduced pressure, theresidue was treated with MeOH (120 mL) and 2 N HCl (40 mL). Theresulting solution was vigorously stirred at room temperature for 24 hand the solvents were removed under reduced pressure. The residue wasextracted twice with CH₂Cl₂, dried over Na₂SO₄. After the solvent wasevaporated under reduced pressure, the residue was purified bychromatography on silica gel eluted with hexanes/ethyl acetate to afford2.9319 g (55% in two steps) of4-(5-bromo-2-fluorobenzoyl)-4-hydroxycyclohexanone. LC-MS t_(R)=1.39 minin 3 min chromatography, m/z 315, 317 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ7.62-7.57 (m, 1H), 7.50-7.47 (m, 1H), 7.08-7.03 (m, 1H), 3.41 (s, 1H),2.83-2.74 (m, 2H), 2.42-2.36 (m, 2H), 2.31-2.23 (m, 2H), 2.14-2.09 (m,2H); ¹³C NMR (100 MHz, CDCl₃) δ 209.51, 204.88 (d, J=2.30 Hz), 157.68(d, J=248.44 Hz), 135.66 (d, J=8.44 Hz), 131.55 (d, J=3.83 Hz), 127.54(d, J=19.17 Hz), 118.07 (d, J=24.53 Hz), 117.19 (d, J=3.84 Hz), 78.07,36.37, 33.89, 33.87; ¹⁹F NMR (376 MHz, CDCl₃) δ −112.90.

Step 3. 5-bromo-3H-spiro[benzofuran-2,1′-cyclohexane]-3,4′-dione

To a solution of 4-(5-bromo-2-fluorobenzoyl)-4-hydroxycyclohexanone(1.0055 g, 3.19 mmol, 1.0 equiv) in THF (30 mL) was added 95% t-BuOK(0.3440 g, 2.91 mmol, 0.9 equiv) portionwise. The resulting mixture washeated at 100° C. for 1 h. The reaction mixture was then cooled with anice bath and quenched with H₂O, extracted with ethyl acetate, dried overNa₂SO₄. After the solvents were evaporated, the residue was purified bychromatography on silica gel eluted with hexanes/ethyl acetate to afford0.3889 g (41%) of5-bromo-3H-spiro[benzofuran-2,1′-cyclohexane]-3,4′-dione as a whitesolid. LC-MS t_(R)=1.58 min in 3 min chromatography, m/z 295, 297 (MH⁺);¹H NMR (400 MHz, CDCl₃) δ 7.82-7.81 (m, 1H), 7.76-7.73 (m, 1H),7.10-7.07 (m, 1H), 2.81-2.72 (m, 2H), 2.60-2.55 (m, 2H), 2.29-2.21 (m,2H), 2.08-2.03 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 208.25, 200.80,169.71, 140.99, 127.47, 121.58, 115.55, 114.81, 88.10, 36.68, 31.86.

Step 4. Synthesis ofcis-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one andtrans-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one

To a solution of5-bromo-3H-spiro[benzofuran-2,1′-cyclohexane]-3,4′-dione (0.2281 g, 0.77mmol) in THF (15 mL) was added NaBH₄ (0.0266 g, 0.70 mmol) portionwiseat −78° C. After 15 min, additional NaBH₄ (0.0138 g, 0.36 mmol) wasadded at −78° C. After 25 min, the reaction mixture was quenched withacetone and stirred at room temperature for 1 h. After the solvents wereevaporated, the residue was purified by chromatography on silica geleluted with hexanes/ethyl acetate to afford 0.0108 g (5%) oftrans-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one and0.1424 g (62%) ofcis-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one.

For trans-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one,LC-MS t_(R)=1.56 min in 3 min chromatography, m/z 297, 299 (MH⁺), 279,281; ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.77 (m, 1H), 7.70-7.66 (m, 1H),7.02-6.99 (m, 1H), 4.18-4.17 (m, 1H), 2.23-2.14 (m, 2H), 2.03-1.87 (m,4H), 1.53-1.49 (m, 2H).

For cis-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one,LC-MS t_(R)=1.47 min in 3 min chromatography, m/z 297, 299 (MH⁺); ¹H NMR(400 MHz, CDCl₃) δ 7.77-7.76 (m, 1H), 7.70-7.67 (m, 1H), 7.05-7.02 (m,1H), 3.83-3.78 (m, 1H), 2.08-2.03 (m, 2H), 1.88-1.72 (m, 6H); ¹³C NMR(100 MHz, CDCl₃) δ 202.30, 169.84, 140.60, 127.21, 121.81, 115.54,114.20, 89.12, 68.73, 30.67, 30.37.

Step 5. synthesis ofcis-5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one

A mixture ofcis-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one(0.1424 g, 0.48 mmol), Ag₂O (0.3800 g, 1.64 mmol), MeI (0.85 mL, 13.6mmol), and Drierite® (0.78 g) in CH₃CN (5 mL) was vigorously stirred atroom temperature for 66 h. The reaction mixture was filtered. After thesolvents were evaporated, the residue was purified by chromatography onsilica gel eluted with hexanes/ethyl acetate to afford 0.1232 g (83%) ofcis-5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one andrecover 0.0220 g (15%) ofcis-5-bromo-4′-hydroxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one.

For cis-5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one,LC-MS t_(R)=1.86 min in 3 min chromatography, m/z 311, 313 (MH⁺); ¹H NMR(400 MHz, CDCl₃) δ 7.68-7.67 (m, 1H), 7.63-7.60 (m, 1H), 6.97 (d, J=8.8Hz, 1H), 3.33 (s, 3H), 3.29-3.22 (m, 1H), 2.08-2.04 (m, 2H), 1.77-1.57(m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 202.15, 169.74, 140.44, 127.07,121.77, 115.48, 114.04, 89.32, 55.70, 30.09, 26.95.

Step 6: Synthesis of intermediate 2

A solution of compound 1 (500 mg, 1.613 mmol), Ti(OEt)₄ (4.58 g, 16.13mmol) and compound 1A (780 mg, 6.45 mmol) in THF (10 mL) was heated atreflux overnight. Then the mixture was partitioned between H₂O (10 mL)and EtOAc (30 mL). The mixture was filtered and the filtrate wasextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative TLC (petroleum:ethyl acetate, 5:1)to give compound 2 (300 mg, 45%) as a yellow solid.

Step 7: Synthesis of intermediate 3

To a solution of compound 2A (183 mg, 0.8 mmol) in THF (2 mL) was addedn-BuLi (0.35 mL, 0.878 mmol) at −78° C. slowly. After being stirred at−78° C. for 30 min, a solution of compound 4 (300 mg, 0.726 mmol) in THF(1 mL) was added dropwise at −78° C. slowly. The mixture was stirred at−78° C. for 2 h, then was allowed to warm to the room temperature andstirred overnight. The mixture was quenched with saturated aqueous NH₄Cl(2 mL). The aqueous layer was extracted with EtOAc (3×20 mL), and thecombined organic layers were washed with brine (15 mL), dried overNa₂SO₄ and concentrated under reduced pressure to give the residue,which was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) and preparativeHPLC to give compound 3 (60 mg, 20%) as a yellow solid.

Step 8: Synthesis of compound 21

A solution containing compound 3 (30 mg, 0.073 mol) and compound 3A (0.2mL, excess) in toluene (2 mL) was deoxygenated by bubbling a stream ofnitrogen through the reaction mixture for 5 min. Then, PdCl₂(PPh₃)₂ (5mg) was added. The reaction vial was sealed and placed into CEMmicrowave reactor and irradiated at 130° C. for 35 min. After beingcooled to room temperature, the mixture was partitioned between EtOAc(20 mL) and aqueous CsF (4 M, 10 mL), and the aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (15 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by preparative TLC(CH₂Cl₂:MeOH, 10:1) and HPLC to give compound 21 (2.0 mg, 8%) as a whitesolid.

LC-MS t_(R)=0.950 min in 2 min chromatography, MS (ESI) ink 399 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.19 (d, J=8.0 Hz, 1H), 7.75-7.83 (m, 2H),7.51 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H),6.87 (s, 1H), 3.33 (s, 3H), 3.00-3.11 (m, 1H), 1.95-2.07 (m, 4H),1.53-1.66 (m, 3H), 1.26-1.37 (m, 2H), 0.81-0.83 (m, 2H), 0.63-0.65 (m,2H).

Example 20 Synthesis of Compound 22

A mixture of compound 3 (20 mg, 0.049 mmol), CuCl (9.7 mg, 0.097 mmol))in DMF (1.5 mL) was placed into CEM microwave reactor and irradiated at170° C. for 40 min. After being cooled to room temperature, the mixturewas partitioned between H₂O (10 mL) and EtOAc (20 mL). The aqueous layerwas extracted with EtOAc (3×20 mL). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by preparative HPLC (acidic) to givecompound 22 (5.3 mg, 30%) as a white solid.

LC-MS t_(R)=0.864 min in 2 min chromatography, MS (ESI) ink 369 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.18 (d, J=7.6 Hz, 1H), 7.85 (t, J=7.6 Hz,1H), 7.77 (t, J=7.2 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.39 (dd, J=2.0,8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 3.33 (s, 3H), 3.18(m, 1H), 2.18-2.23 (m, 1H), 1.96-2.10 (m, 3H), 1.55-1.70 (m, 3H),1.25-1.26 (m, 1H).

Example 21 Synthesis of Compound 23

Procedure for Preparation of Compound 2

To a solution of compound 1A (135 mg, 0.533 mmol) in THF (3 mL) wasadded n-BuLi (0.234 mL, 0.586 mmol) at −78° C. slowly. The reactionmixture was stirred at −78° C. for 30 min, a solution of compound 1 (200mg, 0.484 mmol) in THF (2 mL) was added dropwise to above mixtureslowly. After being stirred at −78° C. for 2 h, the mixture was allowedto warm to the room temperature and stir overnight. Then the mixture wasquenched with saturated aqueous NH₄Cl (2 mL). The aqueous layer wasextracted with EtOAc (3×20 mL), and the combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and concentrated in vacuoto give the residue, which was purified by preparative TLC(CH₂Cl₂:MeOH=10:1) to give compound 2 (42 mg, 20%) as a yellow solid.

General Procedure for Preparation of Compound 23

A mixture of compound 2 (42 mg, 0.096 mmol) and CuCl (19 mg, 0.192mmol)) in DMF (2 mL) was placed into CEM microwave reactor andirradiated at 170° C. for 40 min. After being cooled to roomtemperature, the mixture was partitioned between H₂O (10 mL) and EtOAc(20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄ and concentrated in vacuo to dryness. The residue was purified bypreparative HPLC (acidic) to give compound 23 (3.2 mg, 9%) as a whitesolid.

LC-MS t_(R)=0.920 min in 2 min chromatography, MS (ESI) m/z 390 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.26 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz,1H), 7.89 (s, 1H), 7.33 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.94 (s, 1H),3.21 (s, 3H), 3.08 (m, 1H), 2.00-2.12 (m, 1H), 1.89-1.99 (m, 3H),1.47-1.61 (m, 3H), 1.15-1.22 (m, 2H).

Example 22 Synthesis of Compound 24

This compound was synthesized by method described in Example 19, step 7.The crude product was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) andHPLC to give compound 24 (183 mg, yield 21%) as a yellow solid.

LC-MS t_(R)=1.020 min in 2 min chromatography, MS (ESI) m/z 441/443[M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.08 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.0 Hz,1H), 7.42 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 6.75(s, 1H), 3.33 (s, 3H), 3.23-3.33 (m, 2H), 3.00-3.11 (m, 1H), 1.96-2.05(m, 2H), 1.70-1.71 (m, 1H), 1.45-1.53 (m, 3H), 1.31 (m, 1H); 1.05-1.06(m, 1H).

Example 23 Synthesis of Compound 25

General Procedure for Preparation of Compound 2

To a solution of compound 1 (150 mg, 0.34 mmol) in THF (7.5 mL) wasadded DMAP (63 mg, 0.51 mmol), (Boc)₂O (112 mg, 0.51 mmol) and Et₃N (69mg, 0.68 mmol) at room temperature and the resulting mixture was stirredovernight. The solvent was removed in vacuo to yield the crude compound,which was purified by preparative TLC (petroleum ether:ethylacetate=3:1) to give compound 2 (60 mg, 33%) as a white solid.

General Procedure for Preparation of Compound 3

An oven dried three-necked round bottom flask equipped with condenserwas charged with compound 2 (60 mg, 0.11 mmol), Et₃N (3.6 mL) and Et₂NH(0.7 mL) under N₂ atmosphere. To this solution was added CuI (1 mg,0.0055 mmol) and PdCl₂(PPh₃)₂ (4 mg, 0.0055 mmol). The system wasdegassed once again, then cyclopropyl acetylene (0.6 mL, excess) wasadded and the mixture was stirred at 60° C. (oil bath) overnight. Thesolvent was evaporated in vacuo and the residue was partitioned betweenethyl acetate (2×70 mL) and water (20 mL). The combined organic layerswere washed with brine (30 mL), dried over Na₂SO₄, and concentratedunder reduced pressure to dryness. The crude product was purified bypreparative TLC (petroleum ether:ethyl acetate=3:1) to give compound 3(23 mg, 39%) as a white solid.

General Procedure for Preparation of Compound 25

A solution of compound 3 (23 mg, 0.0218 mmol) in dioxane (5 mL) wasplaced into CEM microwave reactor and irradiated at 120° C. for 15 min.The solvent was removed by evaporation in vacuo to yield the crudecompound, which was purified by HPLC (basic) to give compound 25 (2.4mg, 16%) as a white solid.

LC-MS t_(R)=1.0564 min in 2 min chromatography, MS (ESI) m/z 427.1[M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.050 (d, J=8.8 Hz, 1H), 7.394 (d, J=7.6 Hz,1H), 7.334 (d, J=7.6 Hz, 1H), 7.218 (d, J=2.4 Hz, 1H), 6.802 (s, 1H),6.733 (s, 1H), 3.863 (s, 3H), 3.334 (s, 3H), 3.289 (m, 3H), 2.031 (m,2H), 1.721 (m, 1H), 1.315-1.530 (m, 5H), 1.073 (m, 1H), 0.857 (m, 2H),0.689 (m, 2H).

Example 24 Synthesis of Compound 26

Step 1. Synthesis of Intermediate 2

A mixture of compound 1 (1.5 g, 2.79 mmol), CuCN (0.55 g, 6.11 mmol)) inNMP (4 mL) was heated at 130° C. for 4 h. Then the mixture was cooled toroom temperature, and partitioned between H₂O (20 mL) and EtOAc (30 mL).The aqueous layer was extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=10:1) togive compound 2 (0.8 g, 67%) as a yellow solid.

Step 2. Synthesis of Intermediate Compound 3

To a solution of SnCl₂ (3.34 g, 14.8 mmol) in concentrated HCl (2.7 mL)was added a solution of compound 2 (0.8 g, 3.7 mmol) in 95% ethanol (1.3mL). The resulting mixture was stirred at room temperature for 2 h. TLCshowed the reaction was completed, and the mixture was treated with 50%aqueous NaOH solution (10 mL) to give the yellow solid. The resultingmixture was filtered, and the filter cake was dissolved in CH₂Cl₂ (200mL). The mixture was filtered, and the filtrate was dried over Na₂SO₄and concentrated in vacuo to give compound 3 (0.4 g, 58%) as a yellowsolid.

Step 3. Synthesis of Intermediate 4

To a solution of compound 3 (0.4 g, 2.15 mmol) in concentrated HCl (1mL) was added a solution of NaNO₂ (0.222 g, 3.22 mmol) in H₂O (8 mL)slowly while keeping temperature between −5° C.˜0° C. After addition,the reaction mixture was stirred at 0° C. for 30 min. Then, a solutionof KI (3.57 g, 21.5 mmol) in H₂O (7 mL) was added slowly and stirred foranother 3 h. The resulting mixture was filtered, and the filtrate wasextracted with ethyl acetate (2×100 mL). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give the residue, whichwas purified by column chromatography on silica gel (petroleumether:ethyl acetate=10:1) to give compound 4 (0.6 g, 94%) as a yellowsolid.

Step 4. Preparation of Compound 26

This was synthesized by method described in example 25. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) and HPLC togive compound 26 (2.5 mg, 4%) as a yellow solid.

LC-MS t_(R)=0.949 min in 2 min chromatography, MS (ESI) m/z 479/481[M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.39 (d, J=8.4 Hz, 1H), 8.04 (d, J=7.6 Hz,1H), 7.56-7.59 (m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 3.23-3.33(m, 2H), 3.20 (s, 3H), 3.00-3.11 (m, 1H), 1.86-1.98 (m, 2H), 1.59-1.62(m, 1H), 1.30-1.40 (m, 3H), 1.15-1.29 (m, 1H), 0.92-1.01 (m, 1H).

¹⁹F-NMR (706-182-1J CD₃OD 400 MHz): δ −64.176.

Example 25 Synthesis of Compound 27

This was synthesized by method described in example 14. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) and RP-HPLC(acidic) to yield compound 27 (9.2 mg,) as a white solid.

LC-MS t_(R)=1.058 min in 2 min chromatography, MS (ESI) m/z 465 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.37 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz,1H), 7.56 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.40 (d, J=9.2 Hz, 1H), 6.87(s, 1H), 3.33 (s, 3H), 3.25-3.28 (s, 2H), 3.10 (m, 1H), 1.95-2.07 (m,2H), 1.74-1.76 (m, 1H), 1.36-1.45 (m, 5H), 1.05-1.06 (m, 1H), 0.81-0.86(m, 2H), 0.66-0.68 (m, 2H).

¹⁹F-NMR (CD₃OD 400 MHz): δ −64.198.

Example 26 Synthesis of Compound 28

Step 1. Synthesis of Intermediate 2

To a solution of compound 1 (500 mg, 1.37 mmol) in CH₂Cl₂ (10 mL) wasadded TFA (0.8 mL) at room temperature and stirred overnight, and thenice-water (20 g) was added. The aqueous layer was extracted with CH₂Cl₂(3×20 mL), and the combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo to give the residue, which was purified bypreparative TLC (petroleum:ethyl acetate=5:1) to give compound 2 (300mg, 88%) as a yellow oil.

Step 2. Synthesis of Intermediate 3

To a solution of compound 2 (200 mg, 0.82 mmol) and K₂CO₃ (227 mg, 1.64mmol) in DMF (6 mL) was added compound 2A (165 mg, 1.224 mmol) at roomtemperature and stirred overnight. The solvent was added water (20 mL).The aqueous layer was extracted with EtOAc (3×20 mL), and the combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo to givethe residue, which was purified by preparative TLC (petroleum:ethylacetate=5:1) to give compound 3 (210 mg, 86%) as a yellow oil.

Step 4. Synthesis of Intermediate 4

A solution of compound 3 (210 mg, 0.7 mmol), Ti(OEt)₄ (1.99 g, 7 mmol)and compound 3A (339 mg, 2.8 mmol) in THF (5 mL) was heated at refluxovernight. Then the mixture was partitioned between H₂O (10 mL) andEtOAc (20 mL). The mixture was filtered and the filtrate was extractedwith EtOAc (3×100 mL). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated in vacuo to dryness.The residue was purified by preparative TLC (petroleum:ethylacetate=5:1) to give compound 4 (220 mg, 78%) as a yellow solid.

Procedure for Preparation of Compound 28

To a solution of compound 4A (213 mg, 0.93 mmol) in THF (2 mL) was addedn-BuLi (0.372 mL, 0.93 mmol) slowly at −78° C., and the mixture wasreacted at −78° C. for 30 min. Then to the above mixture was added asolution of compound 4 (75 mg, 0.186 mmol) in THF (1 mL) slowly at −78°C., and the mixture was reacted at −78° C. for 2 h, then slowly warm tothe room temperature and reacted overnight. Then the mixture wasquenched with saturated aqueous NH₄Cl (2 mL). The aqueous layer wasextracted with EtOAc (3×20 mL), and the combined organic layers weredried over Na₂SO₄ and concentrated to give the residue, which waspurified by preparative TLC (CH₂Cl₂:MeOH, 10:1) and HPLC to givecompound 28 (1.7 mg, 2%) as a yellow solid.

LC-MS t_(R)=1.132 min in 2 min chromatography, MS (ESI) m/z 403 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.10 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.2 Hz,1H), 7.64 (t, J=7.2 Hz, 1H), 7.30-7.34 (m, 2H), 6.91 (d, J=2.4 Hz, 1H),6.34 (s, 1H), 3.61-3.70 (m, 2H), 3.23-3.33 (m, 2H), 3.20 (s, 3H),3.00-3.11 (m, 1H), 1.89-2.00 (m, 2H), 1.71-1.74 (m, 1H), 1.40-1.45 (m,3H), 0.97-1.30 (m, 3H), 0.51-0.54 (m, 2H), 0.24-0.25 (m, 2H).

Example 27 Synthesis of Compound 29

This was synthesized as described in example 20. The crude product waspurified by preparative TLC (CH₂Cl₂:MeOH=10:1) and HPLC to give compound29 (25 mg, yield 4%) as a yellow solid.

LC-MS t_(R)=0.959 min in 2 min chromatography, MS (ESI) m/z 412, 414[M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.81 (d, J=5.2 Hz, 1H), 8.59 (s, 1H), 8.05 (d,J=4.8 Hz, 1H), 7.50 (d, J=5.6 Hz, 1H), 7.36 (d, J=5.6 Hz, 1H), 7.06 (s,1H), 3.23-3.33 (m, 2H), 3.20 (s, 3H), 3.00-3.11 (m, 1H), 1.86-1.98 (m,2H), 1.59-1.62 (m, 1H), 1.30-1.40 (m, 3H), 1.15-1.29 (m, 1H), 0.92-1.01(m, 1H).

Example 28 Synthesis of Compound 30

This was synthesized by method described for example 14. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) and HPLC togive compound 30 (3.0 mg, 58%) as a white solid.

LC-MS t_(R)=0.932 min in 2 min chromatography, MS (ESI) m/z 398 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 8.92 (d, J=5.2 Hz, 1H), 8.69 (s, 1H), 8.15 (d,J=5.2 Hz, 1H), 7.45 (dd, J=8.0, 22.0 Hz, 2H), 6.88 (s, 1H), 3.23-3.33(m, 2H), 3.20 (s, 3H), 3.00-3.11 (m, 1H), 1.86-1.98 (m, 2H), 1.59-1.62(m, 1H), 1.30-1.40 (m, 3H), 1.15-1.29 (m, 1H), 0.92-1.01 (m, 1H).

Example 29 Synthesis of Compound 31

To a solution of compound 30 (11 mg, 0.028 mmol) in EtOH (5 mL) wasadded Pd/C (2 mg), the mixture was stirred at room temperature under H₂atmosphere (1 atm) for 1 h. The reaction mixture was filtered through apad of Celite, the filtrate was concentrated in vacuo to give theresidue, which was purified by preparative HPLC to give compound 31 (2.5mg, 22%) as a white solid.

LC-MS t_(R)=1.144 min in 2 min chromatography, MS (ESI) m/z 402 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.94 (d, J=5.2 Hz, 1H), 8.70 (s, 1H), 8.19 (d,J=4.8 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.79 (s,1H) 3.38 (s, 2H), 3.37 (s, 3H), 3.13 (m, 1H), 2.70 (m, 2H), 2.08 (m,2H), 1.83 (m, 1H), 1.56 (m, 6H), 1.39 (m, 1H), 0.67 (m, 1H), 0.38 (m,2H), 0.00 (m, 2H).

Example 30 Synthesis of Compound 32

This was synthesized by method described in example 19, step 7.

LC-MS t_(R)=0.979 min in 2 min chromatography, MS (ESI) m/z 429/431[M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 7.48-7.50 (m, 1H), 7.39-7.41 (m, 1H),7.31-7.33 (m, 1H), 7.22 (t, J=9.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 6.87(s, 1H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 3.03-3.05 (m, 1H), 1.89-1.97(m, 2H), 1.55-1.68 (m, 2H), 1.25-1.42 (m, 3H), 0.98-1.01 (m, 1H).

Example 31 Synthesis of Compound 33

This was synthesized by method described in example 14. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) andpreparative HPLC (acidic) to yield compound 33 (5.1 mg, 19%) as a whitesolid.

LC-MS t_(R)=0.929 min in 2 min chromatography, MS (ESI) m/z 415 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 7.74-7.80 (m, 1H), 7.34-7.43 (m, 3H), 7.16 (d,J=7.6 Hz, 1H), 6.90 (s, 1H), 3.33 (s, 3H), 3.25-3.28 (s, 2H), 3.10 (m,1H), 1.95-2.07 (m, 2H), 1.74-1.76 (m, 1H), 1.33-1.49 (m, 5H), 1.05-1.06(m, 1H), 0.81-0.86 (m, 2H), 0.66-0.67 (m, 2H).

¹⁹F-NMR (CD₃OD 400 MHz): δ −116.633.

Example 32 Synthesis of Compound 34

To a solution of compound 33 (13 mg, 0.03 mmol) in EtOH (5 mL) was addedPd/C (2 mg), the mixture was stirred under H₂ (30 PSI) at roomtemperature for 1 h. Then the mixture was filtered, the filtrate wasconcentrated in vacuo to give the residue, which was purified bypreparative HPLC to give compound 34 (1.0 mg, 8%) as a white solid.

¹H NMR (CD₃OD 400 MHz): δ 7.81 (m, 1H), 7.44 (m, 2H), 7.27 (dd, J=7.6,13.6 Hz, 2H), 6.82 (s, 1H) 3.67 (m, 1H), 3.16 (s, 3H), 3.13 (m, 2H),2.70 (m, 2H), 2.03 (m, 2H), 1.81 (m, 1H), 1.48 (m, 5H), 1.36 (m, 2H),0.66 (m, 1H), 0.38 (m, 2H), 0.00 (m, 2H).

LC-MS t_(R)=1.213 min in 2 min chromatography, MS (ESI) m/z 419 [M+H]⁺.

Example 33 Synthesis of Compound 35

This was synthesized by method described in example 19, step 7. Thecrude product was purified by preparative TLC on silica gel(CH₂Cl₂:MeOH=10:1) and by HPLC (0.1% TFA as buffer) to give compound 35(8.0 mg, 7%) as a white solid.

LC-MS (736-022-1Y): t_(R)=0.830 min in 2 min chromatography, MS (ESI)m/z 436 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.42 (s, 1H), 7.96 (dd, J=1.2, 8.0 Hz, 1H),7.47 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H),3.30 (m, 3H), 3.20 (m, 2H), 3.01 (m, 1H), 1.95 (m, 1H), 1.86 (m, 1H),1.64 (m, 1H), 1.38 (m, 2H), 1.18 (m, 2H), 0.93 (m, 1H).

Example 34 Synthesis of Compound 36

This was synthesized by method described in example 14. The crudeproduct was purified by preparative TLC on silica gel (CH₂Cl₂:MeOH=10:1)and by preparative HPLC (0.1% TFA as buffer) to give compound 36 (7.3mg, 9%) as a white solid.

LC-MS (736-056-1B): t_(R)=0.998 min in 2 min chromatography, MS (ESI)m/z 422 [M+H]⁺.

¹H NMR (CD₃OD 400 MHz): δ 8.52 (s, 1H), 8.04 (dd, J=1.6, 8.0 Hz, 1H),7.53 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.37 (dd, J=1.2, 8.0 Hz,1H), 6.89 (s, 1H), 3.36 (m, 3H), 3.32 (m, 2H), 3.10 (m, 1H), 2.05 (m,1H), 1.95 (m, 1H), 1.74 (m, 1H), 1.31-1.50 (m, 5H), 1.05 (m, 1H), 1.01(m, 2H), 0.85 (m, 2H).

Example 35 Synthesis of Compound 37

Step 1. Synthesis of Compound 2

A mixture of compound 1 (0.8 g, 4.68 mmol) and NH₃/EtOH (10 mL) wasstirred at 60° C. for 6 days. Then the mixture was concentrated in vacuoto give the residue, which was purified by chromatography(petroleum:ethyl acetate=1:1) to give compound 2 (0.44 g, 77%) as awhite solid.

Step 2. Synthesis of Compound 3

A mixture of compound 2 (340 mg, 2.79 mmol), TFAA (0.99 mL) and Et₃N(2.35 mL) in THF (10 mL) was stirred at room temperature for 3 h. Thenthe mixture was concentrated in vacuo to give the residue. The mixturewas partitioned between H₂O (20 mL) and EtOAc (30 mL). The aqueous layerwas extracted with EtOAc (3×30 mL). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and concentrated in vacuoto the crude product, which was purified by preparative TLC (petroleumether:ethyl acetate=1:1) to give compound 3 (160 g, 55%) as a yellowsolid.

Step 3. Synthesis of Compound 37

To a solution of compound 3 (100 mg, 0.89 mmol) in THF (2 mL) was addeddropwise n-BuLi (0.392 mL, 0.98 mmol) at −78° C. slowly. After beingstirred at −78° C. for 30 min, a solution of compound 4 (333 mg, 0.81mmol) in THF (1 mL) was added at −78° C. slowly. After addition, themixture was stirred at −78° C. for another 2 h, then was allowed to warmto room temperature and stirred overnight. The mixture was quenched withsaturated aqueous NH₄Cl (3 mL). The aqueous layer was extracted withEtOAc (3×10 mL), and the combined organic layers were washed with brine(10 mL), dried over Na₂SO₄ and concentrated in vacuo to give theresidue, which was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) andpreparative HPLC to give compound 37 (4.9 mg, 7%) as a yellow solid.

LC-MS t_(R)=0.951 min in 2 min chromatography, MS (ESI) m/z 432/434[M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 7.56 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.4 Hz,1H), 7.09 (s, 1H), 3.33 (s, 3H), 3.23-3.33 (m, 2H), 3.00-3.11 (m, 1H),2.88 (s, 3H), 2.03-2.05 (m, 2H), 1.81 (m, 1H), 1.58 (m, 1H), 1.38-1.43(m, 4H).

Example 36 Synthesis of Compound 38

This was synthesized by method described in example 14. The crudeproduct was purified by preparative TLC (CH₂Cl₂:MeOH=10:1) andpreparative HPLC to yield compound 38 (3.3 mg, 18%) as a white solid.

LC-MS t_(R)=0.916 min in 2 min chromatography, MS (ESI) m/z 418 [M+H]⁺.

¹H-NMR (CD₃OD 400 MHz): δ 7.37 (m, 2H), 6.82 (s, 1H), 3.33 (s, 3H),3.23-3.33 (m, 2H), 3.00-3.11 (m, 1H), 2.88 (s, 3H), 2.03-2.05 (m, 2H),1.81 (m, 1H), 1.58 (m, 1H), 1.38-1.43 (m, 5H), 0.84-0.88 (m, 2H),0.67-0.70 (m, 2H).

Example 37 BACE Enzyme Assay

Inhibitory activity of compounds was assessed by a fluorescence quenchassay of BACE activity using commercially available substrate HiLyteFluor™488-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys-(QXL™ 520)-OH (AnaSpec,San Jose, Calif.) and truncated human beta-secretase (residues 1-458,His₆-tagged at the C-terminus) expressed in insect cells D. melanogasterS2 using a baculovirus expression system (Mallender et al.,Characterization of recombinant, soluble beta-secretase from an insectcell expression system., Mol Pharmacol 59:619-26, 2001). The assay wasperformed at room temperature in 96-well white opaque Optiplates aqueOptiplates (PerkinElmer, Waltham, Mass.) in a total volume of 200 μl ofthe incubation mixture containing 50 mM sodium acetate buffer, pH 4.5,0.4 μM FRET substrate, 2.4 nM enzyme, 5% DMSO, and 0.05% Brij-35. Thetested compounds were serially diluted in DMSO and pre-incubated withthe substrate. The reaction was started by addition of enzyme, and theprogress of the reaction was followed by measuring fluorescence with anexcitation wavelength of 480 nm and an emission wavelength of 520 nm.Ten measurements were taken every 5-10 min, and the intensity offluorescence was regressed against time in order to derive velocities ofreaction in all 96 wells. These velocities were used for calculatingpercent inhibition using an uninhibited control containing 5% DMSO and afully inhibited control incubations performed in the absence of enzyme.IC₅₀ values were calculated by fitting percent inhibition vs. inhibitorconcentration into a four-parametric logistic model using XLFit software(IDBS, Guildford, UK).

Example 38 BACE Assay

For each compound being tested, the BACE activity was monitored in afluorescence quenching assay (FRET) using the ectodomain of BACE (aa1-454) fused to a myc-his tag and secreted from HEK293/BACE_(ect.) cellsinto OptiMEM™ (Invitrogen) as enzyme source and a substrate peptidederived from the APP-Swedish mutation which possesses a Cy3-fluorophoreat the N-terminus and a Cy5Q-quencher at the C-terminus(Cy3-SEVNLDAEFK-Cy5Q-NH2; Amersham). The substrate was dissolved at 1mg/ml in DMSO.

The assay was performed in the presence of 5 μl OptiMEM (supernatantcollected over 24 hours and cleared from cellular debris bycentrifugation) containing the ectodomain of BACE, 25 μl watercontaining the desired concentration of test compound and 1% DMSO, 1 μMsubstrate peptide, 20 mM NaOAc, pH 4.4 and 0.04% Triton-X100 in a totalassay volume of 50 μl in a 384 well plate. In general, 25 μl of compounddilution were given to the plate followed by the addition of 10 μl ofBACE containing OptiMEM™ diluted 1:2 in water with 0.2% Triton X-100.The reaction was started with the addition of 15 μl substrate in NaOAcbuffer. The reaction was incubated at 30° C. in a fluorimeter and thecleavage of the substrate was recorded as kinetic for 60 min. at ex: 530nm, em: 590 nm Blank wells containing either no inhibitor or no enzymewere included on each plate.

The intensity of fluorescence was regressed against time in order toderive velocities of reaction in all 384 wells. These velocities wereused for calculating percent inhibition using an uninhibited controlcontaining 1% DMSO and a fully inhibited control incubations performedin the absence of enzyme. IC₅₀ values were calculated by fitting percentinhibition vs inhibitor concentration using standard software likeGraphPadPrism.

Using this assay protocol, compound dilutions were either done using aTecan Freedom EV0 (assay format A) or manually using multichannelpipettes (assay format B).

Example 39 BACE Activities of Compounds of the Invention

The BACE inhibitor activities of compounds of the invention were testedaccording to protocols described in Example 38 or Example 39, and areshown below:

Compound No. Structure/Example No. IC₅₀ 1

  1.1^(a) 2

  2.19^(a) 3

  9.5^(a) 4

  29^(a) 5

  14^(a) 6

  5^(a) 7

 2816^(a) 8

  7.5^(a) 9

  16.3^(a) 10

 733^(a) 11

 242^(a) 12

50000^(b) 13

  55^(a) 14

  14.5^(b) 15

  6^(b) 16

  47^(b) 17

  3.6^(b) 18

  4.6^(b) 19

  5.9^(b) 20

  20^(b) 21

  74^(b) 22

 413^(b) 23

  83^(b) 24

 1428^(b) 25

  35^(b) 26

  65^(b) 27

  6.5^(b) 28

  13^(b) 29

N/A 30

N/A 31

N/A 32

N/A 33

  5^(b) 34

  13^(b) 35

  24.8^(b) 36

  4.09^(b) 37

N/A 38

N/A ^(a)IC₅₀ values were determined according to protocols described inExample 37. ^(b)IC₅₀ values were determined according to protocolsdescribed in Example 38.

What is claimed is:
 1. A compound represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein: each R⁰ isindependently selected from —H, —CN, —NO₂, halogen, —OR⁵, —NR⁶R⁷,—S(O)_(i)R⁵, —NR¹¹S(O)₂R⁵, —S(O)₂NR¹²R¹³, —C(═O)OR⁵, —OC(═O)R⁵,—C(═S)OR⁵, —OC(═S)R⁵, —C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³,—NR¹¹C(═S)R⁵, —NR¹¹(C═O)OR⁵, —O(C═O)NR¹²R¹³, —NR¹¹(C═S)OR⁵,—O(C═S)NR¹²R¹³, —NR¹¹(C═O)NR¹²R¹³, —NR¹¹(C═S)NR¹²R¹³, —C(═O)R⁵,—C(═S)R⁵, (C₁-C₆)alkyl, (C₃-C₄)cycloalkyl and(C₃-C₄)cycloalkyl(C₁-C₃)alkyl and wherein each (C₁-C₆)alkyl and(C₁-C₃)alkoxy represented by R⁰ are optionally substituted with 1 to 5substituents independently selected from the group consisting ofhalogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy, and —NR⁶R⁷, or two R⁰ together with the ring carbon atomto which they are attached form a (C₃-C₆)cycloalkyl, optionallysubstituted with halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy, and —NR⁶R⁷; R¹ is —H, —OH,—(C₁-C₄)alkoxy, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, wherein each alkyl, aryl and heteroaryl isoptionally substituted with 1 to 5 substituents independently selectedfrom halogen, —CN, —OH, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₃)alkoxyand halo(C₁-C₃)alkoxy; each R² is independently selected from a) —H,halogen, —CN, —NO₂, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(O)₂R⁵,—S(O)₂NR¹²R¹³, —C(═O)OR⁵, —OC(═O)R⁵, —C(═S)OR⁵, —OC(═S)R⁵,—C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —NR¹¹C(═S)R⁵, —NR¹¹(C═O)OR⁵,—O(C═O)NR¹²R¹³, —NR¹¹(C═S)OR⁵, —O(C═S)NR¹²R¹³, —NR¹¹(C═O)NR¹²R¹³,—NR¹¹(C═S)NR¹²R¹³, —C(═O)R⁵, —C(═S)R⁵; and b) (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl(C₂-C₆)alkynyl,(C₄-C₈)cycloalkenyl, (C₃-C₉)heterocycloalkyl,(C₃-C₉)heterocycloalkyl(C₁-C₆)alkyl,(C₃-C₉)heterocycloalkyl(C₂-C₆)alkynyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₂-C₆)alkynyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, andheteroaryl(C₂-C₆)alkynyl, wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(C₂-C₆)alkynyl, (C₄-C₈)cycloalkenyl,(C₃-C₉)heterocycloalkyl, (C₃-C₉)heterocycloalkyl(C₁-C₆)alkyl,(C₃-C₉)heterocycloalkyl(C₂-C₆)alkynyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₂-C₆)alkynyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, andheteroaryl(C₂-C₆)alkynyl is optionally substituted with 1 to 5substituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —OR⁵, —NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(O)₂R⁵,—S(O)₂NR¹²R¹³, —C(═O)OR⁵, —OC(═O)R⁵, —C(═S)OR⁵, —OC(═S)R⁵,—C(═O)NR¹²R¹³, —NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —NR¹¹C(═S)R⁵, —NR¹¹(C═O)OR⁵,—O(C═O)NR¹²R¹³, —NR¹¹(C═S)OR⁵, —O(C═S)NR¹²R¹³, —NR¹¹(C═O)NR¹²R¹³,—NR¹¹(C═S)NR¹²R¹³, —C(═O)R⁵, —C(═S)R⁵, (C₁-C₆)alkyl, (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₈)cycloalkenyl, (C₃-C₉)heterocycloalkyl,(C₂-C₆)alkenyl, halo(C₁-C₆)alkyl,—(C₁-C₆)alkylene-NR¹¹—SO₂—(C₁-C₃)alkyl, hydroxy(C₁-C₆)alkyl,cyano(C₁-C₆)alkyl, —(C₁-C₆)alkylene-NR¹¹—C(═O)—(C₁-C₃)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₆)alkoxy(C₁-C₃)alkyl, aryl, andheteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl andheteroaryl groups in the substituents on the groups represented by R₂are each optionally substituted with 1 to 3 substituents independentlyselected from halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy and (C₁-C₃)alkoxy(C₁-C₆)alkyl; R⁵ isselected from the group consisting of —H, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkyl and phenyl optionally substituted withhalogen, —CN, —NO₂, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl or(C₁-C₃)alkoxy(C₁-C₃)alkyl; R⁶ is —H or (C₁-C₃)alkyl; R⁷ is —H,(C₁-C₃)alkyl, halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl; Ring A is a3-9 membered cycloalkyl optionally substituted with 1 to 4 substituentsindependently selected from the group consisting of halogen, —CN, —OR⁵,—NR⁶R⁷, —S(O)_(i)R⁵, —NR¹¹S(═O)₂R⁵, —C(═O)OR⁵, —C(═O)NR¹²R¹³,—NR¹¹C(═O)R⁵, —C(═S)NR¹²R¹³, —C(═O)R⁵, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,aryl, aryl(C₁-C₆)alkyl, heteroaryl and heteroaryl(C₁-C₆)alkyl, whereineach of the (C₁-C₆)alkyl, (C₂-C₆)alkenyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl substituents on Ring A isoptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of (C₁-C₆)alkyl, halogen, —CN, —OH,—NR¹¹SO₂(C₁-C₃)alkyl, —NR¹¹C(═O)—(C₁-C₃)alkyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy and (C₁-C₃)alkoxy(C₁-C₆)alkyl, andwherein Ring A is optionally fused to a phenyl group optionallysubstituted with 1 to 5 substituents independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, —CN, —OH,—NR¹¹SO₂(C₁-C₃)alkyl, —NR¹¹C(═O)—(C₁-C₃)alkyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy and (C₁-C₃)alkoxy(C₁-C₆)alkyl; R¹¹ is —Hor (C₁-C₃)alkyl; R¹² is —H or (C₁-C₃)alkyl; R¹³ is —H, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl(C₁-C₃)alkyl or(C₁-C₃)alkoxy(C₁-C₃)alkyl; d is an integer from 1 to 6; i is 0, 1 or 2;and p is 1, 2, 3 or
 4. 2. The compound of claim 1, wherein: R¹ is a —Hor a (C₁-C₃)alkyl; each R² is independently selected from the groupconsisting of —H, halogen, —CN, —NO₂, —OR⁵, —C(═O)NR¹²R¹³, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₄-C₈)cycloalkenyl, phenyl, pyridyl, thiazolyl, pyridazinyl,pyridazinone, pyridinone, thiophenyl, pyrrolyl, pyrimidinyl, pyrazinyl,indolyl, pyrrolidinyl, piperazinyl and morpholinyl, each of the(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl(C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₄-C₈)cycloalkenyl, phenyl, pyridinyl, thiazolyl,pyridazinyl, pyridazinone, pyridinone, thiophenyl, pyrrolyl,pyrimidinyl, pyrazinyl, indolyl, pyrrolidinyl, piperazinyl andmorpholinyl is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halogen, —OH, —CN,—NO₂, (C₁-C₆)alkyl, (C₂-C₆)alkynyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, (C₁-C₃)alkoxy(C₁-C₆)alkyl, —NR⁶R⁷ and—SO₂R⁵; and each R⁰, when present, is independently selected from thegroup consisting of —H, halogen, —CN, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₃)alkoxy and —NR⁶R⁷, or two R⁰, taken together to the carbon atomto which they are attached, form a (C₃-C₆)cycloalkyl.
 3. The compound ofclaim 2, wherein: each R² is independently selected from —Br, —Cl, —CN,—OR⁵, (C₁-C₆)alkyl, (C₂-C₆)alkynyl, phenyl and pyridinyl, wherein eachof the (C₁-C₆)alkyl, (C₂-C₆)alkynyl, phenyl and pyridinyl is optionallysubstituted with 1 to 3 substituents independently selected from —F,—Cl, —Br, —CN, (C₃-C₆)cycloalkyl, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy and halo(C₁-C₃)alkoxy.
 4. The compound of claim 3,wherein: R¹ is —H; each R² is independently selected from the groupconsisting of —Br, —Cl, —CN, cyclopropylethyl, cyclopropylethynyl,cyclopropylmethoxy, 5-trifluoromethyl-2-pyridyl, 2-pyridyl,3-chloro-5-fluorophenyl, 3-cyanophenyl, 3-trifluoromethoxyphenyl andmethoxy; and each R⁰, when present, is independently selected from thegroup consisting of —H, —F, —CN, -Me, -Et, —OMe, —CF₃ and —NH₂, or twoR⁰ together with the carbon atom to which they are attached form acyclopropyl ring.
 5. The compound of claim 4, wherein: R⁵ is selectedfrom the group consisting of —H, -Me, —CF₃ and cyclopropylmethyl; andR⁶, R⁷, R¹¹, R¹² and R¹³ are all —H.
 6. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier or diluent and acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 7. Amethod of treating a BACE mediated disorder in a subject comprisingadministering to the subject an effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof, wherein the BACEmediated disorder is selected from the group consisting of Alzheimer'sdisease, Down's Syndrome, cerebral amyloid angiopathy, glaucoma,HCHWA-D, cognitive impairment and cognitive decline.
 8. The method ofclaim 7, wherein the disorder is Alzheimer's disease.
 9. The method ofclaim 7, wherein the disorder is glaucoma.
 10. A compound represented byany one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.